Devices and methods for treating motion sickness using electrical stimulation

ABSTRACT

In an illustrative embodiment, systems and methods for providing antiemetic therapy through neuromodulation include positioning a first electrode against or at least partially into a first tissue region on or surrounding a subject&#39;s ear such that the first electrode is on, over, or adjacent to one or more first neural structures, positioning a second electrode against or at least partially into a second tissue region on or surrounding the ear such that the second electrode is on, over, or adjacent to one or more second neural structures, delivering a first series of stimulation pulses to the first electrode for modulating peripheral activity via modulating central neural autonomic structures, and delivering a second series of stimulation pulses to the second electrode for increasing availability of central norepinephrine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 63/346,697 entitled “Devices and Methods for Treating MotionSickness Using Electrical Stimulation” and filed May 27, 2022. Thisapplication is related to U.S. Patent Application Publication No.2023/0149703 entitled “Devices and Methods for Treating Stress andImproving Alertness Using Electrical Stimulation,” U.S. Pat. No.11,623,088 entitled “Devices and Methods for the Treatment of SubstanceUse Disorders,” U.S. Pat. No. 11,351,370 entitled “Devices and Methodsfor Treating Cognitive Dysfunction and Depression using ElectricalStimulation,” U.S. Pat. No. 10,967,182 entitled “Devices and Methods forReducing Inflammation Using Electrical Stimulation,” and U.S. Pat. No.10,695,568 entitled “Device and Method for the Treatment of SubstanceUse Disorders.” All above identified applications are herebyincorporated by reference in their entireties.

BACKGROUND

Motion sickness is a common and complex syndrome that occurs in responseto real or perceived motion. Motion sickness is triggered when animbalance in the autonomic nervous system is generated by a mismatchbetween incoming and expected sensory inputs. The incoming sensoryinputs include vestibular, visual, and somatosensory inputs. Thismismatching scenario results in a response that involves importantautonomic circuits in the brain such as hypothalamic, histaminergic,norepinephrine (NE) as well as cholinergic circuits. The overallautonomic response manifests as motion sickness. Sub-conditions ofmotion sickness include, e.g., terrestrial motion sickness (e.g., in acar, an airplane, or at sea), simulator motion sickness (e.g., virtualreality environments) and space motion sickness (e.g., in microgravityenvironments).

Common symptoms of motion sickness include cold sweats, nausea,vomiting, dry heaves, headache, dizziness, lightheadedness, spinningsensation, fatigue, irritability, drowsiness, salivation, vertigo, andspatial disorientation, among others. In some cases, people sufferingfrom motion sickness may experience what is called sopite syndrome,which consists of profound drowsiness and fatigue, apathy, depression,disinclination for work, decreased participation in group activities,malaise, lethargy and agitation that can persist for hours to days afterthe motion sickness triggering event. In other cases, sufferers continueto feel movement after there is no longer motion, which is known as malde debarquement (MDD). Motion sickness has also been sometimesconceptualized as a poison response, with corresponding autonomicresponses including a stress response and an emesis response.

Consequences of motion sickness scenarios can range from a passenger ina cruise ship feeling sick to an astronaut endangering a space mission,as well as, for example, a commercial or military airplane pilotendangering his or her life along with that of their passengers. Motionsickness that leads to spatial disorientation may result in aviationmishap.

There are several interventions currently being used to counteractmotion sickness symptoms. Antihistamine drugs, particularly centrallyacting antihistamines that cross the blood-brain-barrier, are the mostcommon approach. For example, antihistamine interventions that limit theactivity at HI receptors (HI antagonists) in the CNS have been shown tobe effective against motion sickness, e.g., Dimenhydrinate (i.e.,Dramamine®). However, these interventions have an undesirable sedativeeffect, which, in many scenarios typical of various motion sicknesssub-conditions (e.g., an airplane pilot or an eSport athlete on avirtual reality platform), is entirely prohibitive.

Anticholinergic as well as adrenergic/sympathomimetics agents may alsobe effective in overcoming the autonomic imbalance manifested as motionsickness. Anticholinergic agents have been shown to be effective inpreventing motion sickness. Although the specific mechanisms of actionhave not been fully identified, evidence suggests that theanticholinergic agents act on hippocampal circuits to impair thecomparison between expected and actual sensory inputs and thereby reducemismatch signaling. As with antihistamines, however, anticholinergicagents also produce an undesirable sedative effect.

Sympathomimetics interventions such as amphetamines have been shown tobe effective in treating motion sickness. Data suggests that neuralmismatch signaling reduces the availability of norepinephrine (NE) byGABAergic inhibition of Locus Coeruleus (LC) neuronal activity.Sympathomimetics interventions, which tend to increase NE availability,are thought to counteract GABAergic inhibition. However, prolonged useof sympathomimetics substances may lead to addiction. In some scenariosunder which a sedative effect is not desirable, a combination of ananticholinergic and a sympathomimetic are used. For example, duringspace flights a combination of scopolamine (anticholinergic) anddextroamphetamine (sympathomimetic) is commonly used.

There are other less common pharmacological interventions used to treator that have the potential to treat motion sickness. For example,rizatriptan, a serotonin 1B/1D receptor agonist used to treat migraine,has been shown to prevent motion sickness in prone migraine individuals.Other serotonin 5-HT receptor agonists, e.g., 5-HT 1A receptor agonists,have also shown anti motion sickness effects. Neuronal activity in thevestibular nuclei has been shown to be downregulated by 5-HT 1Aagonists, suggesting that the action of 5-HT in the vestibular nucleiattenuates incoming vestibular sensory signals that may trigger motionsickness.

Another medication that may help alleviate motion sickness symptoms isLoperamide, which is a synthetic antidiarrheal. Loperamide is aperipherally acting μ-opioid receptor agonist which has been shown toreduce rotational induced motion sickness.

In general, drug therapies are often inadequate and too slow acting totreat acute motion sickness symptoms in real time. Moreover, sideeffects such as drowsiness, decreased cognitive and motor skills,sedation, or inattentiveness prevent their use in some occupations. Fewmotion sickness sufferers or their prescribing physician would use drugtherapies with addictive consequences as their first choice; in fact,many would prefer not to use this type of therapy at all.

SUMMARY OF ILLUSTRATIVE EMBODIMENTS

The inventors recognized the use of noninvasive neuromodulation ofcranial nerves would be a highly beneficial primary or augmentedtreatment for motion sickness. In one aspect, the therapy system andmethods of the present disclosure relate to reducing or eliminatingsymptoms of motion sickness through neuromodulation (e.g., vagal and/ortrigeminal stimulation). In another aspect, the therapy system andmethods of the present disclosure relate to inhibiting the physiologicaltriggers of motion sickness through neuromodulation. Thus, the methodsand systems described herein may both attend symptoms as well as limitthe triggering of motion sickness. Although described in relation tomotion sickness, therapies, systems, and apparatus described herein mayadditionally be used to treat the symptoms and/or triggers of certaintypes of vertigo.

Using the therapy systems and methods described herein, motion sicknessmay be treated on several fronts. In some embodiments, the system andmethods of the present disclosure are effective at modulating productionof NE through activation of LC neurons, resulting in increasedavailability of central NE. The increase in central NE availabilityproduces a similar effect to that of the sympathomimetics interventions,for example by counteracting GABAergic inhibition of LC-NE circuitsmanifested in motion sickness. Accordingly, the systems and methods ofthe present disclosure may be used in lieu of, or in combination with,such pharmacological treatments.

In some embodiments the system and methods of the present disclosureincrease 5-HT availability as activity in the RN is upregulated. Thisincrease in 5-HT is qualitatively comparable with Rizatriptan-basedtherapy, discussed above. Data suggests that activation of VestibularNuclei (VN) afferent serotonergic neurons from the RN produces aninhibitory effect in VN activity, which, in turn, decreases the VNefferent signals involved in the triggering of motion sickness.Accordingly, the systems and methods of the present disclosure may beused in lieu of, or in combination with, such pharmacologicaltreatments.

Furthermore, the systems and methods of the present disclosure, in someembodiments, modulate central neural autonomic structures (CNAS) toproduce a whole body response by triggering or by modulating peripheralactivity. For example, an increase in pituitary activity via theParaventricular Hypothalamic Nucleus (PVN), both the pituitary and thePVN being example CNAS, produces an increase in peripheral circulatingβ-endorphins, thus modulating peripheral activity in many organs thathave β-endorphin receptors. This mimics the above-mentionedpharmacological intervention with Loperamide. Thus, as explained above,embodiments of the present disclosure may qualitatively mimic at leastthree pharmacological interventions that are known to have a positiveoutcome when treating motion sickness. In another example, CNAS such asthe NTS can be modulated to effectively modulate peripheral activity inthe spleen, thus triggering a whole-body anti-inflammatory response. Inyet another example, modulation of the Nucleus Ambiguus (NA), which is aCNAS, can lead to an increase in parasympathetic tone, thus activating aperipheral cardiovascular response. In an additional example, modulationof the LC (a CNAS) can modulate peripheral activity at the adrenalmedulla, thus increasing catecholamines circulation.

In some implementations, the therapy system includes a treatment devicethat allows the proposed therapy to be easily and reliably applied byalmost anyone at a relatively low cost. Some advantages of the treatmentdevice, in addition to those described above, include ease of use inboth the application of the device, customizing therapeutic settings,and the actual wearing of the device, minimal risk of infection, usershave the ability to safely self-administer or restart the treatmentwithout the oversight of a clinician.

In a preferred embodiment, a therapy system includes a treatment devicehaving an auricular component configured to be in contact with a patientand a pulse generator or controller configured to communicate with thetreatment device. In some implementations, a treatment device can beprovided as an assembled unit or as several pieces configured forconnection prior to use. In an example, the auricular component can beprovided in a sealed pouch and a pulse generator can be provided toconnect the auricular component to a connector on the pulse generator.In an aspect, the system is configured to have a removable stimulatorwithout the need to remove the auricular component and vice-versa. In anexample, the earpiece can be placed around the auricle of the patientbefore or after connection to the pulse generator.

In some implementations, the treatment device can be used to providetherapy including a neurostimulation configured to stimulate pathwaysmodulating endogenous 5-HT release. In some implementations, thetreatment device can be used to provide therapy including a firstneurostimulation configured to stimulate pathways modulatingcatecholamine release, including the release of norepinephrine. In someimplementations, the treatment device can be used to provide therapyincluding a neurostimulation configured to stimulate pathways modulatingendorphin release. In some implementations, the treatment device can beused to provide therapy including a neurostimulation configured tostimulate pathways modulating release of one or more of endogenous 5-HT,catecholamines, and/or endorphins. In some implementations, thetreatment device can be used to provide therapy including a plurality ofneurostimulations configured to stimulate pathways modulating release oftwo or more of endogenous 5-HT, catecholamines, and/or endorphins.

In an example, a first neurostimulation can be a low frequencystimulation and a second neurostimulation can be a high frequency. In anexample, the pathways modulating 5-HT and/or catecholamine release caninclude at least one of the auricular branches of the vagus nerve, thelesser occipital nerve, and the great auricular nerve. In an example,the pathways modulating endorphins release can include stimulation ofendorphins pathway via stimulation of the Arcuate nucleus of thehypothalamus.

To provide the therapy, a provider or user may adjust therapy parametersas needed and start the therapy using the controls on either the pulsegenerator or the peripheral device. In some implementations, the therapyincludes providing two or more simultaneous and/or synchronized, and/orinterleaved stimulations. In an aspect, the therapy can involve applyinga first stimulation having a first set of parameters at a first portionof the patient's skin and applying a second stimulation having a secondset of parameters at a second portion of the patient's skin. Whentherapy is done, the user may remove the earpiece and disconnect theearpiece from the pulse generator. In an example, the used earpiece canbe replaced with a new earpiece for the next session.

In some embodiments, the earpiece and the pulse generator are integratedin the form of a single component, such that the pulse generator, aswell as its power source (e.g., battery) are located in the same housingas the earpiece.

In some embodiments, treatment can be applied unilaterally (left orright) and yet in other embodiments a bilateral treatment may beapplied. In the case of a bilateral application two devices could beused; these two devices could be synchronized for yet a better systemicresponse. A single device with more channels or a single devicemultiplexing the outputs could also be used for a bilateral application.

One of the advantages of the systems and methods of the presentdisclosure over these pharmacological interventions is that they are notsystemically administered. Moreover, the systems and methods have noknown side effects such as, e.g., drowsiness and sedation, and they arenot addictive.

The therapeutic methods, systems, and devices of the present disclosuremay be applied in a variety of circumstances and used by variousindividuals. For example, the therapeutic methods, systems, and devicesmay be used by ship or other watercraft passengers or personnel;airplane pilots, crew or passengers; spacecraft astronauts (e.g., spaceadaptation syndrome or “space sickness”); or drivers and passengers ofautomobiles or other land-based transportation. The therapeutic methods,systems, and devices may be used in different environments and undervarious conditions. For example, the therapeutic methods, systems, anddevices may be used by astronauts in a space environment under highradiation conditions. The therapeutic methods, systems, and devices maybe used by pilots or flight trainees at altitude and/or under highG-force conditions. The therapeutic methods, systems, and devices mayalso be used in wet conditions, e.g., in connection with use on and/orunder the water, such as by scuba divers. The therapeutic devices mayinclude differing design elements based on the conditions of use. Forexample, a device for use in high G-force may include elements forensuring tight contact and secure placement of the therapeutic device.In another example, a device for use in water operations such as amilitary beach landing or scuba mission may include waterproofingelements to ensure utility of the device under wet conditions. Thetherapeutic methods, systems, and devices may be used either in actualor simulated conditions involving situations, vessels, and/or eventscommonly leading to motion sickness symptoms. The therapeutic methods,systems, and devices, in some examples, may be used by an e-athleteduring competition, by military or astronaut personnel during trainingand/or active missions, and/or by pilots during flights or flightsimulation training. The therapeutic methods, systems, and devices maybe administered in various ways. For example, the therapeutic methods,systems, and devices described herein may be used in real-time to treatsymptoms of motion sickness or prophylactically to prevent motionsickness. The therapeutic methods, systems, and devices may be employedin a method of treatment administered by a clinician or other healthprofessional or directly by the user with or without medicalsupervision.

At least a therapeutic delivery portion of treatment device, in someembodiments, is attached to or integrated with a head-mounted device orsystem. For example, electrodes and pulse delivery circuitry may beconnected to or built into a head-mounted device or system. Thehead-mounted device or system, in some examples, may include a virtualreality (VR) helmet, VR goggles, a protective helmet (e.g., a pilothelmet, a military helmet, a crash helmet, etc.), a protective helmetwith VR heads-up display, a space helmet to be worn by an astronaut, ora communications headset. The pulse generator and/or controller, forexample, may be separate from the head-mounted device or system or alsointegrated into the head-mounted device or system. The head-mounteddevice or system may be augmented by therapeutic neuromodulation tosupport a wearer of the head-mounted device or system during activitieswhere the head-mounted device or system is needed, such as whilepiloting a plane, maneuvering in microgravity, or participating in a VRtraining exercise involving significant motion simulation.

Chemotherapy is known to induce nausea and vomiting in cancer patients(i.e., chemotherapy-induced nausea and vomiting or CINV). There areseveral pharmacotherapies used to prevent and treat CINV. However,despite advancements, more than 30% (in some cases up to 60%), of cancerpatients undergoing chemotherapy experience CINV. CINV can lead tosevere consequences including non-compliance with the cancer treatment.Among other, current treatments include pharmacologic agents withantiemetic and anxiolytic effects. Both effects can be attained viavagal stimulation; furthermore, an anti-anxiety effect has also beenshown by trigeminal stimulation. The therapeutic methods, systems, anddevices described herein may be used to prevent and/or treat CINV byapplying stimulation before, during, and/or after the chemotherapysession.

The forgoing general description of the illustrative implementations andthe following detailed description thereof are merely exemplary aspectsof the teachings of this disclosure and are not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate one or more embodiments and,together with the description, explain these embodiments. Theaccompanying drawings have not necessarily been drawn to scale. Anyvalues dimensions illustrated in the accompanying graphs and figures arefor illustration purposes only and may or may not represent actual orpreferred values or dimensions. Where applicable, some or all featuresmay not be illustrated to assist in the description of underlyingfeatures. In the drawings:

FIG. 1A and 1B are drawings identifying example neural structures andpathways for delivering therapeutic treatment for motion sickness;

FIG. 2A illustrates example connections of theHypothalamic-Pituitary-Adrenal (HPA) Axis pathway;

FIG. 2B illustrates example connections of theSympathetic-Adrenomedullary (SMA) Axis pathway;

FIG. 3A illustrates example connections of the main parasympatheticpathway;

FIG. 3B illustrates example connections of the central endorphinpathway;

FIG. 4A illustrates example connections of a stress reduction pathway;

FIG. 4B illustrates example connections of an arousal and alertnesscontrol pathway;

FIG. 4C illustrates example connections of an anti-inflammatory pathway;

FIG. 5A illustrates example mechanisms for using electrical stimulationto control and/or decrease stress;

FIG. 5B illustrates example mechanisms for using electrical stimulationto promote wakefulness, increase arousal/alertness, and counteractfatigue;

FIG. 5C illustrates example mechanisms for using electrical stimulationto for decrease pro-inflammatory processes;

FIG. 6A and FIG. 6B illustrate an example electrode configuration andequivalent circuits for providing therapy;

FIG. 7 illustrates an example timing diagram for supplying stimulationpulses a an auricular therapeutic device;

FIGS. 8A-8B illustrate a first example auricular therapeutic device;

FIGS. 9A-9C illustrate a second example auricular therapeutic device;

FIGS. 10A-10C are drawings of example systems including an exampletreatment device in communication with remote systems through acomputing cloud and/or a peripheral device;

FIG. 11 is a block diagram of components of an example pulse generatorin communication with an example auricular therapy device;

FIG. 12 illustrates example pathways in the autonomic nervous systeminvolved in triggering motion sickness;

FIG. 13 illustrates example connections of a motion sicknessintervention pathway;

FIG. 14 illustrates example mechanisms for using electrical stimulationto treat motion sickness;

FIG. 15 illustrates an example wearable auricular neuro-stimulation(WANS) apparatus; and

FIG. 16A through FIG. 16D, FIG. 17 , and FIG. 18 illustrate exampletarget nerve regions for directing therapy using a WANS apparatus.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The description set forth below in connection with the appended drawingsis intended to be a description of various, illustrative embodiments ofthe disclosed subject matter. Specific features and functionalities aredescribed in connection with each illustrative embodiment; however, itwill be apparent to those skilled in the art that the disclosedembodiments may be practiced without each of those specific features andfunctionalities.

Reference throughout the specification to “one embodiment” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with an embodiment is included inat least one embodiment of the subject matter disclosed. Thus, theappearance of the phrases “in one embodiment” or “in an embodiment” invarious places throughout the specification is not necessarily referringto the same embodiment. Further, the particular features, structures orcharacteristics may be combined in any suitable manner in one or moreembodiments. Further, it is intended that embodiments of the disclosedsubject matter cover modifications and variations thereof.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context expressly dictates otherwise. That is, unlessexpressly specified otherwise, as used herein the words “a,” “an,”“the,” and the like carry the meaning of “one or more.” Additionally, itis to be understood that terms such as “left,” “right,” “top,” “bottom,”“front,” “rear,” “side,” “height,” “length,” “width,” “upper,” “lower,”“interior,” “exterior,” “inner,” “outer,” and the like that may be usedherein merely describe points of reference and do not necessarily limitembodiments of the present disclosure to any particular orientation orconfiguration. Furthermore, terms such as “first,” “second,” “third,”etc., merely identify one of a number of portions, components, steps,operations, functions, and/or points of reference as disclosed herein,and likewise do not necessarily limit embodiments of the presentdisclosure to any particular configuration or orientation.

Furthermore, the terms “approximately,” “about,” “proximate,” “minorvariation,” and similar terms generally refer to ranges that include theidentified value within a margin of 20%, 10% or preferably 5% in certainembodiments, and any values therebetween.

All of the functionalities described in connection with one embodimentare intended to be applicable to the additional embodiments describedbelow except where expressly stated or where the feature or function isincompatible with the additional embodiments. For example, where a givenfeature or function is expressly described in connection with oneembodiment but not expressly mentioned in connection with an alternativeembodiment, it should be understood that the inventors intend that thatfeature or function may be deployed, utilized or implemented inconnection with the alternative embodiment unless the feature orfunction is incompatible with the alternative embodiment.

In some implementations, treatment systems, devices, and methods forstimulation of neural structures on and surrounding a patient's ear aredesigned for providing stimulation without piercing the dermal layers onor surrounding the ear (e.g., transcutaneous stimulation). Electrodesmay be frictionally and/or adhesively retained against the skin on andsurrounding the patient's ear to target various nerve structures. Theelectrodes may have a substantial surface area in comparison to priorart systems relying upon dermal-piercing electrodes, such that multiplenerve terminals are stimulated by a single electrode during therapy. Forexample, a number of nerve terminals may be situated directly beneathand/or beneath and closely adjacent to the skin upon which the electrodeis positioned. By targeting multiple nerve terminals, in someembodiments, positioning of each electrode does not necessarily need tobe precise. Therefore, for example, a patient or caregiver may be ableto apply and remove the device as desired/needed (e.g., for sleeping,showering, etc.). Further, targeting multiple nerve terminals isadvantageous since stimulating multiple branches of a nerve elicits astronger response than stimulating a single branch, which is the casewhen using pinpoint electrodes such as needle electrodes.

Although example implementations described herein relate to auriculartranscutaneous stimulation, transcutaneous access to target nervestructures, such as vagal and trigeminal nerves and/or nerve branches,is not limited to the auricular branch of the vagus nerve (ABVN) and theauriculotemporal nerve. For example, the vagus nerve, as it ascendsinside the carotid sheath along the neck, approaches the subcutaneousregion. Trigeminal nerves approach the subcutaneous region at severallocations in the face; for example, the supraorbital nerve,supratrochlear nerve, Infratrochlear nerve, the palpebral branch of thelacrimal nerve, the external nasal nerve, the infraorbital nerve, thezygomaticofacial nerve, the zygomaticotemporal nerve, the mental nerve,and the buccal nerve are potential trigeminal targets to delivertranscutaneous stimulation. A device enabling positioning of electrodesagainst a subject's skin such that any of these branches is stimulated,for example, may trigger responses related to trigeminal stimulationdescribed below. In illustration, a device enabling stimulation of oneor more of the above-noted branches may be used to reduce bleed timeand/or bleed volume when stimulating in a prophylactic fashion and/orafter an injury that has caused bleeding to occur. For example, a devicesuch as the one described by Simon, et al, in U.S. Pat. No. 10,207,106could be utilized to trigger a vagal response. In a similar manner, thedevice such as that described by Rigaux in U.S. Pat. No. 8,914,123 canbe used to trigger such responses. Furthermore, it is recognized thatboth devices could be used simultaneously or in an alternative manner toelicit a vagal, a trigeminal, or a trigeminal-vagal response.

In some implementations, methods described herein for stimulation ofneural structures on and surrounding a patient's ear may be appliedusing devices designed for providing percutaneous stimulation. Forexample, electrodes having tissue-penetrating portions and/or electrodesdesigned to penetrate tissue (e.g., needle electrodes) may be insertedin a minimally invasive manner (e.g., through at least a top dermallayer of a patient's skin). An example percutaneous auricularstimulation device is the P-STIM® device by Biegler GmbH, described, forexample, in U.S. Pat. No. 10,058,478 to Schnetz et al., incorporatedherein by reference in its entirety. Percutaneous stimulation, in otherembodiments, may be performed at other locations on a subject's skin,for example including the regions described above in relation totranscutaneous stimulation.

In some embodiments, vagal neural structures can be activated bymodulating the cervical vagus as it ascends along the neck vianon-penetrating and/or penetrating electrodes.

FIG. 1A and FIG. 1B illustrate example neural structures and pathwaysuseful in embodiments disclosed herein for deriving benefits throughnerve stimulation. Turning to FIG. 1A, the Nucleus Tractus Solitarius(NTS) 104 receives afferent connections from many areas including theTrigeminocervical Complex (TCC) 102, the cervical vagus nerve 128, aswell as from the auricular branch of the vagus nerve (ABVN) 118. The TCC102 is a region in the cervical spinal cord in which spinal cervicalnerves from C1, C2, and C3 converge with sensory trigeminal fibers. Inthe region of the TCC 102, the trigeminal and occipital fibers synapse,including the Auriculotemporal Nerve 130, the lesser occipital nerve152, and the greater auricular nerve 154 (e.g., Cervical Spinal 148).The TCC 102 projects to multiple areas in the brain stem including, butnot limited to parts of the Raphe nuclei (hereafter Raphe Nucleus (RN)106), the Locus Coeruleus (LC) 108, Periaqueductal Gray (PAG) 110,Nucleus Basalis (NBM) 120, the Nucleus Ambiguus (NA) 122, the VentralTegmental Area (VTA) 124, the Nucleus Accumbens (NAc) 126, Parabrachialnucleus (PbN) 114, and, as mentioned above, to the NTS. The NTS 104among others, also projects to the RN 106 the LC 108, and the PAG 110 aswell as to higher centers like the hypothalamus 132, including into theArcuate Nucleus (ARC) 112 which receives its majority ofnon-intrahypothalamic afferents from the NTS 104. Cells in the ARC 112are the main source of endorphins in the Central Nervous System (CNS).

The medulla oblongata (medulla) is the lower region of the brainstemcontaining important neuronal structures (nuclei) modulating, forexample, several important involuntary actions such as respiration,heart rate, and blood pressure. The medulla contains several importantnuclei (medullary nuclei) such as the NTS 104, the spinal trigeminalnucleus, the NA 122, and at least some of the RN 106. Additionally, manyinterconnections exist amongst different brainstem nuclei (e.g., PAG110, LC 108, RN 106, NBM 120, PbN 114, Pedunculopontine Nucleus (PPN)116, NA 122, VTA 124, NAc 126). For example, the LC 108, PAG 110, and RN106 project to the NA 122, and the PPN 116 projects into the VTA 124.The VTA 124, in turn, projects to the Prefrontal Cortex 136, beinginterconnected with the hypothalamus 132 and the hippocampus 138. TheVTA 124 projects directly to the Hippocampus 138 as well. TheHippocampus 138, in turn, projects to the NAc 126 and interconnects withthe hypothalamus 132. The following table presents a listing of opioidreceptors in the central nervous system:

TABLE 1 Endogenous Receptor Expression/Distribution Cell Types Ligands(affinity) MOR Amygdala 149, thalamus, periaqueductal GABAergicβ-endorphin (High) gray 110, locus coeruleus 108, nucleus Glutamatergicenkephalins (Med) raphe magnus, mesencephalon, habenula, Dynorphin (Low)hippocampus 138, some brainstem nuclei KOR Basal anterior forebrain,olfactory Dopaminergic Dynorphin (High) tubercle, striatum (caudateputamen and Glutamatergic β-endorphin (Low) NAc 126), preoptic area,hypothalamus GABAergic enkephalins (Low) 132, pituitary DOR Olfactorytract, cortices, including whole GABAergic β-endorphin (High) neocortexand regions of the amygdala Dopaminergic enkephalins (High) 149 thatderive from the cortex Dynorphin (Low) (basolateral, cortical, andmedian nuclei of the amygdala 149), striatum NOP Periaqueductal gray110, thalamic nuclei, Dopaminergic Orphanin FQ/ somatosensory cortex,rostral ventral nociceptin (High) medulla, spinal cord, dorsal rootganglia, VTA 124, NAc 126, PFC, central amygdala, lateral hypothalamusMOR/KOR/DOR = μ/κ/δ-opioid receptor; NOP = nociception/orphanin FQreceptor; NAc = nucleus accumbens; PFC = prefrontal cortex; VTA =ventral tegmental area. Affinity is presented in parenthesis.

These connections make this neural circuit extremely important formodulating pain, as production of endorphins, enkephalins, anddynorphins are modulated by this circuit. In addition, these neuralcircuits are crucial for learning and memory as well as for arousal andwakefulness. For example, an interaction between norepinephrine,produced by activity in the Locus Coeruleus (LC) 108, Serotonin (5-HT),produced by activity in the RN, and Acetylcholine (ACh) produced byactivity in the Pedunculopontine Nucleus (PPN) 116 or NBM 120 isextremely important for memory and learning. Arousal and wakefulness aremodulated, amongst others, by catecholamines in the brain, such asnorepinephrine and dopamine.

There are descending indirect connections (e.g., via efferent pathways139) going to the heart 140, lungs 142, gut 144, and spleen 146.Indirect connections include connections where there is at least onesynapse elsewhere before reaching the target. This means that modulatingthe activity of these neural circuits can affect the respective organs.In particular, heart rate can be modulated (e.g., heart rate can bedecreased and heart rate variability can be increased); oxygenabsorption can be increased at the lungs 142 by increasing thecompliance of the bronchi tissue and thus increasing the oxygentransport availability therefore increasing the potential for moreoxygen to be absorbed into the blood; gut motility can be increased bydescending pathways originating in the dorsal motor nucleus of the vagusnerve (DMV) 304 of FIG. 3B; since DMV activity is modulated by NTSactivity, motility in the gut 144 can be affected by modulating theactivity in the NTS 104; and a decrease in circulating pro-inflammatorycytokines can be achieved by modulating spleen 146 activity via NTS 104descending pathways.

Turning to FIG. 1B, as shown in a block diagram 150, the vagus nerve 156is a cranial nerve that which on its path can be located adjacent to thecarotid artery in the neck. Direct stimulation of the vagus nerve 156activates the nucleus tractus solitarius (NTS) 104, which hasprojections to nucleus basalis (NBM) 120 and locus coeruleus (LC) 108.The NBM 120 and LC 108 are deep brain structures that releaseacetylcholine and norepinephrine, respectively, which are pro-plasticityneurotransmitters important for learning and memory. Stimulation of thevagus nerve 156 using a chronically implanted electrode cuff is safelyused in humans to treat epilepsy and depression and has shown success inclinical trials for tinnitus and motor impairments after stroke. Theauricular branch of the vagus nerve 158 innervates the dermatome regionof outer ear, being the region known as the cymba conchae one of theareas innervated by it. Non-invasive stimulation of the auricular branchof the vagus nerve 158 may drive activity in similar brain regions asinvasive vagus nerve stimulation. Auricular neurostimulation has provenbeneficial in treating a number of human disorders.

Turning to FIG. 2A and FIG. 2B, the response to a stressor, (i.e., thestress response) is carried out via two main pathways: theSympathetic-Adrenomedullary (SMA) Axis 202 and theHypothalamic-Pituitary-Adrenal (HPA) Axis 204. Although many brainregions or nuclei are involved in the stress response, the LocusCoeruleus (LC) 108 and the Paraventricular Hypothalamic Nucleus (PVN)206 (PVN 113 of FIG. 1A) are the two main drivers of these pathways.Modulating central neural autonomic structures (CNAS) along either orboth of these main pathways may produce a whole-body response bytriggering or by modulating peripheral activity.

The LC 108 is the main producer of Norepinephrine (NE) in the CentralNervous System (CNS) and is one of the main drivers of the sympatheticnervous system (SNS). In response to a stressor, the LC 108 releases NE.

In responding to a stressor, the PVN 206 produces, amongst others,Corticotropin (also written as Corticotrophin) Releasing Hormone (CRH),also known as Corticotropin Releasing Factor (CRF). CRH is delivered toseveral brain nuclei, including the LC 108, as well as to the pituitarygland 208 which consequently releases, amongst others, β-endorphins 210and adrenocorticotropic hormone (ACTH) 212 into the blood steam. Thecirculating ACTH 212 reaches the adrenal gland (adrenal cortex) 214 andtriggers the release of Epinephrine (Epi), NE, and glucocorticoids intothe blood stream, in particular cortisol 216 in humans. In general, theEpi/NE ratio released by the adrenals is 80/20.

Epi and NE primarily elicit a sympathetic response (e.g., increase heartrate). Cortisol 216 has various physiologic effects, includingcatecholamine release (e.g., Epi, NE, etc.), suppression of insulin,mobilization of energy stores through gluconeogenesis andglycogenolysis, as well as the suppression of the immune-inflammatoryresponse. In addition, cortisol 216 serves as a feedback molecule-signalto limit the further release of CRH, thus slowing down the stressresponse.

The β-endorphins 210 released from the pituitary gland 208 bind opioidreceptors primarily in the peripheral nervous system (but also to immunecells), where, amongst other effects, they produce analgesia. Thisanalgesia is the result of a cascade of interactions resulting ininhibition of the release of tachykinins, particularly of substance P,which is involved in the transmission of pain.

The PVN 206 receives stress-related ascending monosynaptic afferentsignals from several areas/nuclei. These nuclei include the Nucleus ofthe Solitary Track (NTS) 104, the LC 108, the parabrachial nuclei (PbN)114, the Periaqueductal Grey Area (PAG) 110, and the Raphe Nucleus (RN)106. These ascending pathways carry information regarding the stressoror stressors encountered. In addition to these ascending afferentsignals, intrahypothalamic as well as descending afferent signalsmodulate the PVN 206 response to stressors. For example, signals fromthe Prefrontal cortex (PFC) 218, the Hippocampus (Hipp) 138, and theAmygdala 149 reach the PVN 206; in some cases, these signals are furtherintegrated at the Bed Nucleus of the Stria Terminalis (BNST) beforereaching the PVN 206. Together, these signals incorporate cognitive andmemory information into the stress response.

Turning to FIG. 3A and FIG. 3B, psychological stressors are perceivedand interpreted in an anticipatory fashion, and the response can beheavily modulated by the reward circuit, which includes the PFC 218, theAmygdala 149, the Ventral Tegmental Area (VTA) 306, as well as theNucleus Accumbens (NAc) 126 (dopaminergic pathways, which are highlymodulated by the central endorphin pathway 302). Under normalcircumstances, the Pre-Limbic (PL) and Infra-Limbic (IL) areas of thePFC 218 coordinate a top-bottom control over the stress response topsychological stressors. However, under high stress levels or chronicstress scenarios this top-bottom control gets disrupted and a bottom-topcontrol, heavily weighing the Amygdala's inputs, takes over the stressresponse to these psychological stressors. Having a bottom-top typeresponse hinders the decision-making processes by not given properweight to other signals; for example, to those afferent signals from thePFC 218 and the hippocampus 138.

The brain areas or nuclei forming the neural circuitry involved in thestress response are not only involved in depression but also areintegral components of the Endogenous Opioid Circuit (EOC), whichincludes the Central Endorphin Pathway (FIG. 3B) as well as thesecondary connections arising from it. As illustrated in FIG. 3B,together with FIGS. 2A and 2B, the NTS 104, LC 108, PbN 114, PAG 110, RN106, PFC 218, VTA 306, NAc 126 (as it receives afferents from the VTA306), the Amygdala 149 are part of the EOC. The central endorphinpathway 302 interacts with several other brain regions or nucleiincluding with other hypothalamic areas such as the PVN 206. Stimulatingafferent pathways to the central endorphin pathway 302 such as vagaland/or trigeminal structures activates this circuit and connectedregions, including the VTA 306, which is one of the main producers ofdopamine in the CNS. By activating the central endorphin pathway 302 andconnected regions, systems and methods described herein are able tomodulate stress and alertness levels.

As stated before, one of the characteristics of stress is a hyperactiveSNS, a hypoactive parasympathetic nervous system (PNS), or both;resulting in a high SNS/PNS activity ratio. An increase in the activityof the PNS leads to a faster return to baseline after a response to astressor. One way to increase PNS activity is to increase vagal tonewhich can be achieved by increasing the activity of the Vagus nerve 156.Activation of The Main Parasympathetic Pathway 300 of FIG. 3A results inan increase in vagal tone and thus a better stress response. Amongst themain vagus nerve afferent pathways are those originating in the NTS 104,the NA 122, and the DMV 304. Activity in these regions generally resultsin an increase in vagal tone. Activation of the ABVN 118 and theauriculotemporal nerve (ATN) 130 directly and indirectly lead toincrease activity in all three above mentioned pathways going from theNTS 104, the DMV 304, and the NA 122, to the Vagus nerve 156. As seen inFIG. 3A these pathways also involve other nuclei or regions such as LC108, PAG 110, RN 106, and TCC 102.

As can be seen from a comparison of the stress reduction pathway 400 ofFIG. 4A with the main parasympathetic pathway 300 of FIG. 3A and thecentral endorphin pathway 302 of FIG. 3B, significant overlap exists.Turning to the stress reduction pathway 400 and arousal/alertnesscontrol pathway 402, stimulation (e.g., of the ABVN 118 and/or ATN 130)can be provided to trigger Neuropeptide S (NPS) release into several CNSregions 404. In the CNS, NE is primarily produced in the LC 108. NPS isproduced in the LC 108, the trigeminal nucleus, and the ParabrachialNucleus (PbN) 114. Neuropeptides as opposed to neurotransmitters requirea higher level of activity to be released (e.g., higher frequency ofneuronal activity at the production sites). The NPS release 404, forexample, includes release via the TCC 102, the PbN 114, and the LC 108.

LC 108 activity is key for arousal. Both Norepinephrine 408 and NPS,which are produced in and around the LC 108, promote arousal andwakefulness. Thus, turning to FIG. 4B, interventions that increase NEand NPS in the CNS 404 also increase arousal, mitigating the effects offatigue.

Descending pathways from the LC 108 directly activate sympatheticpreganglionic neurons in the spinal cord (e.g., Coeruleo-SpinalPathway). Activation of these sympathetic spinal neurons has a netsympathetic effect, such as for example an increase in heart rate. Manyof the generalized sympathetic effects are a direct effect of the higheramount of circulating catecholamines, in particular epinephrine andnorepinephrine. The main source of these catecholamines is the adrenalmedulla 412, which is innervated by preganglionic sympathetic nerves410. The adrenal medulla 412 releases a mix of approximately 80%epinephrine and 20% norepinephrine 408 into the blood stream whenstimulated.

Heart rate variability (HRV) is a reflection of the state of theautonomic nervous system (ANS). The sympathetic branch of the ANS, whichis more active during stressful situations, tends to increase heart rate(HR) and decrease HRV; the opposite is true for the parasympatheticbranch of the ANS, which tends to decrease HR and increase HRV. HigherHRV has been associated with well-being and has been used as a healthbiomarker.

In some implementations, an anti-inflammatory effect is provided viaactivation of an anti-inflammatory pathway 420 (e.g., the cholinergicanti-inflammatory pathway), as illustrated in FIG. 4C. In particular,the methods and devices described herein may activate theanti-inflammatory pathway by stimulating the ABVN 118 and/or the ATN 130which, as stated before, have projections to the NTS 104. Theseprojections elicit cholinergic anti-inflammatory effects via efferentpathways, mostly via the vagus nerve 156. Systemic anti-inflammatoryeffects occur when the vagus nerve 156 mediates spleen 146 function,thereby reducing the amount of circulating pro-inflammatory cytokines.In addition, a local anti-inflammatory effect occurs at organs reachedby the efferent pathways, such as at the lungs 142, gut 144, and heart140.

Decreasing systemic pro-inflammatory processes and/or pro-inflammatoryprocesses in one or more target organs 140, 142, 144, and/or 146, insome implementations, involves modulating at least a portion of theanti-inflammatory pathway 420 such that activity at the NTS 104 ismodulated affecting activity in efferent pathways through the celiacganglion 422 and/or the parasympathetic ganglion 424, which in turnmodulate activity in the spleen 146, lungs 142, gut 144, and/or heart140 such that an anti-inflammatory response is elicited.

In some embodiments, the anti-inflammatory pathway 420 may be activatedto reduce bleeding. For example, activation of a portion of theanti-inflammatory pathway 420, via stimulation of the vagus nerve 156,is discussed in U.S. Pat. No. 8,729,129 to Tracey et al., incorporatedby reference herein in its entirety.

Turning to FIG. 5A, a stimulation flow diagram 500 illustratesstimulation mechanisms for controlling and/or decreasing stress 510using a treatment device such as a treatment device 800 of FIG. 8A or atreatment device 900 of FIG. 9A. The stimulation mechanisms are producedby a first stimulation 502 a and a second stimulation 502 b. The firstand second stimulations, in some embodiments, are temporally separated(e.g., in overlapping or non-overlapping stimulations). In someembodiments, the first and second stimulations are physically separated(e.g., using a different electrode or set of electrodes contacting adifferent location on the patient). The first and second stimulations,for example, may be provided via the stress reduction pathways 400discussed in relation to FIG. 4A. According to the pathways 400, thefirst stimulation 502 a and/or the second stimulation 502 b may beconfigured to stimulate the ABVN 118 which projects to the prefrontalcortex and/or the ATN 130 which has a pathway to the prefrontal cortex136 via the TCC 102.

Responsive to a first stimulation 502 a, in some embodiments,parasympathetic activity and/or vagal tone is increased (504). Forexample, Enkephalins may increase BDNF mRNA expression in thehippocampus mediated by DOR and MOR mechanisms while β-Endorphin,endomorphin-1 and endomorphin-2 upregulate BDNF mRNA in the prefrontalcortex, hippocampus and amygdala. Production of dopamine (DA) in theVentral Tegmental Area (VTA) 124 can be augmented by an increase in MORagonist (e.g., endorphins and enkephalins); in particular by inhibitingGABAergic interneurons which in turn inhibit dopaminergic neurons in theVTA. Amongst other, these DAergic VTA neurons project to NucleusAccumbens (NAc) 126, the Prefrontal Cortex (PFC) 136, the Hippocampus(Hipp) 138, and the Amygdala (Amyg) 149. These brain regions also shareprojections/connections amongst themselves making an important neuronalcircuit known as the Reward Circuit or Reward Neural Circuit.Alterations leading to dysregulation, maladaptive regulation, ordysfunctional interactions in this neural circuit are seen in peoplewith behaviors such as addiction, anxiety disorders including PTSD, anddepression. Furthermore, dysregulation in this circuit has also beenobserved in people showing behaviors associated with lower attentionlevels, for example in attention deficit disorder (ADD) and attentiondeficit hyper-activity deficit disorder (ADHD).

Further, in some implementations, the first stimulation 502 a increasesactivity in one or more neural medullary structures 506 a, such as theNTS 104, the spinal trigeminal nucleus, the NA 122, and at least some ofthe RN 106. The first stimulation 502 a, for example, may increaseavailability 506 b, leading to an increase in BDNF expression. The BDNF,in turn, may function to protect monoamine neurotransmitter neurons andassist the monoamine neurotransmitter neurons to differentiate. In someembodiments, the second stimulation 502 b also increases 5-HTavailability.

NPS is mainly produced in three areas in the brain: LC 108, PbN 404 b,and the trigeminal nucleus, the latter being the target of the ATN 130and at least partially included in the TCC 102. Activity in any of thesethree areas is necessary for NPS expression 404. In someimplementations, the second stimulation 502 b increases activity inneural structures in the TCC 508 a. The second stimulation 502 b, forexample, may increase NPS release 508 b via the activation cascade thatfollows the stimulation of the ATN 130.

In some embodiments, providing the first stimulation 502 a and providingthe second stimulation 502 b involves providing a series of simultaneousand/or synchronized, and/or interleaved stimulation pulses. Each of thefirst stimulation 502 a and the second stimulation 502 b may be appliedusing the same or different parameters. The parameters, in someexamples, may include pulse frequency (e.g., low, mid-range, high, orvery high) and/or pulse width. Further, the parameters may indicateelectrode pairs for producing biphasic pulses. In a first illustrativeexample, the first stimulation may be applied using a low frequency,while the second stimulation is applied using a mid-range or highfrequency. Conversely, in a second illustrative example, the firststimulation may be applied using a mid-range frequency, while the secondstimulation is applied using a low frequency. Other combinations of low,mid-range, high, and/or very high frequency stimulations are possibledepending upon the patient and the disorder being treated. Therapy maybe optimized according to the needs of individual patients includingcustom stimulation frequency, custom pulse width, custom stimulationintensity (amplitude), and/or independently controlled stimulationchannels.

Turning to FIG. 5B, a stimulation flow diagram 520 illustratesstimulation mechanisms for promoting wakefulness and increasingarousal/alertness to counteract fatigue 528 using a treatment devicesuch as a treatment device 800 of FIG. 8A or a treatment device 900 ofFIG. 9A. The stimulation mechanisms are produced by a first stimulation522 a and a second stimulation 522 b. The first and second stimulations,in some embodiments, are temporally separated (e.g., in overlapping ornon-overlapping stimulations). In some embodiments, the first and secondstimulations are physically separated (e.g., using a different electrodeor set of electrodes contacting a different location on the patient).The first and second stimulations, for example, may be provided via thearousal alertness/control pathways 402 discussed in relation to FIG. 4B.According to the pathways 402, the first stimulation 522 a and/or thesecond stimulation 522 b may be configured to stimulate the ABVN 118which projects to the prefrontal cortex and/or the ATN 130 which has apathway to the prefrontal cortex via the TCC 102.

Responsive to a first stimulation 522 a, in some embodiments, 5-HT andNE availability are increased (524), leading to an increase in BDNFexpression. The BDNF, in turn, may function to protect monoamineneurotransmitter neurons and assist the monoamine neurotransmitterneurons to differentiate. In some embodiments, the second stimulation522 b also increases 5-HT and NE availability. NE and 5-HT arerespectively produced in the Locus Coeruleus (LC) 108 and in the RapheNucleus (RN) 106. These brain regions are integral parts of theEndogenous Opioid Circuits (EOC). Activity in these brain regions (orbrain areas) can be modulated by activating afferent pathways to the EOCsuch as some trigeminal and vagal branches.

Further demonstrating the previously mentioned link between the EOC,cognition, and depression, studies have shown that some antidepressantspromote neurogenesis likely via the upregulation of Brain-DerivedNeurotrophic- Factor (BDNF) in areas such as the hippocampus 138 and theprefrontal cortex (PFC) 136. BDNF plays a strong role in cognition,plasticity, neurogenesis, and neuronal survival. 5-HT has also beenshown to have a role in such physiological activities. Furthermore,patients suffering from depression have been shown to have decreasedplasma levels of BDNF, suggesting that depressive conditions wouldbenefit from a therapy that could increase BDNF levels. Additionally,learning and memory as well as cortical plasticity is modulated bystimulation of vagal afferents through the synergetic action of ACh,5-HT, NE, and BDNF. Further, acute vagal stimulation has been shown toincrease NE and 5-HT release in the PFC 136 and the amygdala 149 as wellas to enhance synaptic transmission in the hippocampus 138.

The cognitive improvement due to the increase in BDNF, which leads to afaster reorganization of neural circuits, can be leveraged not only tolearn new things faster, but also to eliminate/extinguish undesirableand/or maladaptive behavior such as, in some examples, PTSD, phobias,and addictive behavior such as drug-seeking or overeating.

Also, it has been shown that vagal activation produces pairing-specificplasticity, thus stimulation of vagal afferents, irrespective of whatneuromodulator is produced, can be used to eliminate and/or extinguishundesirable and/or maladaptive behavior such as those described above.Furthermore, trigeminal stimulation has been shown to help and protectcognitive function. Thus, as with vagal afferent activation, activationof trigeminal afferents can be utilized to conserve and promotecognitive performance.

In another example, the cognitive enhancement provided by the systemsand methods described herein can be used to overcome the cognitiveproblems that have been described to occur in people exposed tomicrogravity environments such as astronauts in the space station or ona long space travel such as visiting Mars.

Additionally, BDNF levels have been shown to have an inverse correlationwith factors associated with cognitive decline and/or impediments, suchas in Alzheimer's patients.

The second stimulation 522 b, in some embodiments, increases NPS release526. As discussed above, this increase in NPS production or expressionis the result of the activation cascade that follows the stimulation ofthe ATN 130.

In some embodiments, providing the first stimulation 522 a and providingthe second stimulation 522 b involves providing a series of simultaneousand/or synchronized and/or interleaved stimulation pulses. Each of thefirst stimulation 522 a and the second stimulation 522 b may be appliedusing the same or different parameters. The parameters, in someexamples, may include pulse frequency (e.g., low, mid-range, or high)and/or pulse width. Further, the parameters may indicate electrode pairsfor producing biphasic pulses. In a first illustrative example, thefirst stimulation may be applied using a low frequency, while the secondstimulation is applied using a mid-range or high frequency. Conversely,in a second illustrative example, the first stimulation may be appliedusing a mid-range frequency, while the second stimulation is appliedusing a low frequency. Other combinations of low, mid-range, high,and/or very high frequency stimulations are possible depending upon thedisorder being treated. Therapy may be optimized according to the needsof individual patients including custom stimulation frequency, custompulse width, custom stimulation intensity (amplitude), and/orindependently controlled stimulation channels.

Turning to FIG. 5C, a stimulation flow diagram 530 is illustrated forproviding therapy to decrease systemic pro-inflammatory processes and/orpro-inflammatory processes in one or more target organs. The targetorgans, for example, may include the spleen, lungs, gut, and heart. Thestimulations of flow diagram 530, in some examples, may be applied inmitigating bleeding, reducing volume of bleeding, and/or reducing a timeperiod of blood loss. The stimulations of flow diagram 530, for example,may be performed at least in part by a pulse generator.

In some implementations, a first stimulation 532 is provided at a firsttissue location configured to stimulate the anti-inflammatory pathway420 for decreasing systemic pro-inflammatory processes and/orpro-inflammatory processes in one or more target organs 536. Thepathways, for example, may include a portion of the pathways illustratedin FIG. 4C. The first tissue location, for example, may include asurface of an ear structure contacted by an in-ear component of anauricular stimulation device. In some embodiments, the first stimulation532 is supplied to multiple tissue locations. For example, the firststimulation 532 may be applied to a first tissue location including asurface of an ear structure contacted by an in-ear component of anauricular stimulation device as well as to a second tissue location onthe tragus of the ear.

Decreasing systemic pro-inflammatory processes and/or pro-inflammatoryprocesses in one or more target organs 536, in some implementations,involves modulating at least a portion of the anti-inflammatory pathwayof FIG. 4C such that activity at the NTS 104 is modulated affectingactivity in efferent pathways through the celiac ganglion 422 and/or theparasympathetic ganglion 424, which in turn modulate activity in thespleen 146, lungs 142, gut 144, and/or heart 140 such that ananti-inflammatory response is elicited.

In some implementations, a second stimulation 534 is provided at asecond tissue location configured to stimulate the anti-inflammatorypathway 420 for decreasing systemic pro-inflammatory processes and/orpro-inflammatory processes in one or more target organs 536. Examples oftarget pathways and structures for stimulation of the second tissuelocation include those modulating activity at and/or on theauriculotemporal nerve (ATN) 130, the lesser occipital nerve 152, and/orthe great auricular nerve 154. The pathways, for example, may include aportion of the pathways illustrated in FIG. 5C.

In some embodiments, providing the first stimulation 532 and providingthe second stimulation 534 involves providing a series of simultaneousand/or synchronized, and/or interleaved stimulation pulses to both thefirst tissue location and the second tissue location. Each of the firststimulation 532 and the second stimulation 534 may be applied using thesame or different parameters. The parameters, in some examples, mayinclude pulse frequency (e.g., low, mid-range, or high) or pulse width.Further, the parameters may indicate electrode pairs for producingbiphasic pulses. In a first illustrative example, the first stimulationmay be applied using a low frequency, while the second stimulation isapplied using a mid-range or high frequency. Conversely, in a secondillustrative example, the first stimulation may be applied using amid-range frequency, while the second stimulation is applied using a lowfrequency. Other combinations of low, mid-range, high, and/or very highfrequency stimulations are possible depending upon the patient and thedisorder being treated.

In other embodiments, the therapy provided by the stimulation 532 and/orthe stimulation 534 of the stimulation flow diagram 530 includesautomatically adjusting delivery of the therapy (e.g., adjusting one ormore parameters) based on feedback received from the pulse generator oranother computing device in communication with the pulse generator. Thefeedback, in some examples, may include a blood oxygen concentration, abreathing rate, a breathing variation, tidal volume, skin conductance,blood pressure, heart rate, heart rate variability, pupillometry, and/orEEG signal.

In further embodiments, combinations of the stimulations described instimulation flow diagrams 500 and/or 520 with the stimulations describedin stimulation flow diagram 530 may be used to enhance stress reductionthrough reducing the time and/or volume of the physical stressor ofbleeding. Thus, activation of the anti-inflammatory pathway 420 incombination with activation of the stress reduction pathway 400 of FIG.4A may mitigate stress reactions in subjects experiencing physicalstress at least partially induced by bleeding. In a further example, insubjects performing stressful activities that have a substantiallikelihood of resulting in bleeding (e.g., certain athletes, militarypersonnel involved in active missions, etc.), activating theanti-inflammatory pathway 420 prior to initiation of bleeding maydecrease or minimize bleeding if it occurs and may be used incombination with activation of the arousal/alertness control pathway 402to improve performance, reduce tunnel vision, and maintain focus of thesubject during the activity.

For example, the first stimulation 532 of the stimulation flow diagram530 may be delivered synchronously, simultaneously or interleaved withthe second stimulation 502 b of the stimulation flow diagram 500 of FIG.5A for controlling and/or decreasing stress 510 or vice-versa.Similarly, for example, the first stimulation 532 of the stimulationflow diagram 530 may be delivered synchronously, simultaneously, orinterleaved with the second stimulation 522 b of the stimulation flowdiagram 520 of FIG. 5B for promoting wakefulness, increasingarousal/alertness, and counteracting fatigue 528 or vice-versa. Inanother example, the therapy of the stimulation flow diagram 500,including both the first stimulation 502 a and the second stimulation502 b may be delivered for a first period of time, and the therapy ofthe stimulation flow diagram 530, including both the first stimulation532 and the second stimulation 534 may be delivered for a second periodof time; or the therapy of the stimulation flow diagram 520, includingboth the first stimulation 522 a and the second stimulation 522 b may bedelivered for a first period of time, and the therapy of the stimulationflow diagram 530, including both the first stimulation 532 and thesecond stimulation 534 may be delivered for a second period of time. Thecombined therapies, in some embodiments, may be repeated for a number ofcycles of the first period of time and the second period of time. Basedon feedback, the length of one or both of the first period of time andthe second period of time may be adjusted to control/decrease stress 510or promote wakefulness, increase arousal/alertness, and counteractfatigue 528 while decreasing systemic pro-inflammatory processes and/orpro-inflammatory processes in one or more target organs 536 in anefficient manner.

Turning to FIG. 6A and FIG. 6B, an example electrode configuration of anearpiece device 600 and example equivalent circuits 610 a-b forproviding therapy are shown. Turning to FIG. 6A, the earpiece device600, in some implementations, includes inner ear component electrode602, and auricular component electrodes 604, 606, and 608. Circuitryconnecting between the electrodes 602, 604, 606, and 608 may beconfigured to form corresponding circuits 610 a and 610 b, asillustrated in FIG. 6B.

Turning to FIG. 6B, an equivalent circuit 610 a is formed by electrode602 and electrode 606 which are configured to stimulate tissue portions620. In some implementations, the inner ear component electrode 602 isconfigured to contact a tissue portion 620 in the cymba conchae regionwhich is enervated by branches of the auricular branch of the vagusnerve. The auricular component electrode 606, in some implementations,is configured to contact a tissue portion 620 in the region behind theear which is enervated by branches of the great auricular nerve and/orbranches of the lesser occipital nerve.

An equivalent circuit 610 b is formed by electrode 604 and electrode 608of the auricular component of the device 600 and configured to stimulatetissue portions 622. In some implementations, the tissue portions 622are in the region rostral to the ear which is enervated by theauriculotemporal nerve as well as the region behind the ear which isenervated by branches of the great auricular nerve and branches of thelesser occipital nerve.

In further implementations, the tissue portions include the concha whichmay be stimulated, for example, at approximately 5 Hz or atapproximately 15 Hz, or at approximately 30 Hz In other implementations,the tissue portions include tissue enervated by the trigeminal nervewhich may be stimulated, for example, at approximately 100 Hz.

In some embodiments, the equivalent circuit 1210 a is stimulated by afirst channel and equivalent circuit 1210 b is stimulated by a secondchannel. FIG. 7 pictures a timing diagram 700 illustrating thetriggering of multiple channels 704 and 706 using a master clock 702according to an example. In some embodiments, the clock 702 triggerspulses 708 at a predetermined clock frequency. In an example, a firstchannel 704 can be configured to trigger stimulation of equivalentcircuit 610 a and a second channel 706 can be configured to triggerstimulation of equivalent circuit 610 b of FIG. 6B. Conversely, thetriggering can be reversed, for example, where equivalent circuit 610 bis triggered before equivalent circuit 610 a.

In some implementations, stimulation is configured to be triggered byevery pulse of the master clock 702; i.e., at a 1-to-1 ratio. In someembodiments, stimulation by one channel 704, 706 is configured to betriggered following a specific time interval after the pulse triggeredby the other channel 704, 706 ends. In some embodiments, one of thechannels 704, 706 is configured to be triggered based on every otherpulse of the master clock; i.e., at a 2-to-1 ratio with the masterclock. For example, the triggering by the second channel 706, as shownoccurs every other clock cycle and after a specific time delay 714 fromthe master clock pulse 708. In other embodiments, stimulation by thesecond channel 706 may be configured to be triggered following aspecific time interval after the pulse triggered by the first channel704 ends. In some embodiments, stimulation from one channel 704, 706 isoffset from stimulation by the other channel 704, 706 by a synchronousdelay. As illustrated, the synchronous delay 714 is 2 ms and can be aslittle as zero (making both channels to trigger simultaneously dependingon the master clock ratio for each channel) and as much as the masterclock period less the combined duration of the stimulations provided bychannel 704 and 706 plus the time interval between them. In someembodiments, this delay can be about 10 ms.

In some implementations, the equivalent circuits 610 a, 610 b aresynchronized using a master clock counter and a register per channel. Bysetting each register to a number of master clock pulses to trigger therespective channel, each channel may be configured to be triggered whenthe channel register value equals the master clock pulses. Subsequently,the counter for each channel may be reset after the channel istriggered. In an example, using a 6-bit counter and a 6-bit register,the trigger frequency can be as high as the master clock frequency (1:1)and as low as 1/64 of the clock frequency (64:1).

In some embodiments in which stimulation is applied at more than onesite (e.g., directed to two or more nerve branches, etc.) thestimulation duration, the frequency, the pulse width, and/or the dutycycle may differ across stimulation sites. In some embodiments, in fact,it is beneficial to use different frequencies at different stimulationsites.

Stimulation delivery may vary based upon the therapy provided by thetreatment device. Frequency and/or pulse width parameters, for example,may be adjusted for one or more stimulation sites at which stimulationis being delivered.

In some embodiments, frequency and/or pulse width parameters areadjusted during therapy, for example responsive to feedback receivedfrom monitoring the patient. For example, feedback may be obtained usingone or more sensors or other devices assessing heart rate, bloodpressure, blood oxygen concentration, skin impedance, Electromyography(EMG), pupillometry, and/or motion.

In some embodiments, stimulation pulses are delivered in pulse patterns.Individual pulses in the pattern may vary in frequency and/or pulsewidth. Patterns may be repeated in stimulation cycles. The pulsepattern, for example, may be designed in part to ramp up stimulation,establishing a comfort level in the wearer to the feel of thestimulation. In another example, the pulse pattern may be designed inpart to alternate stimulation between stimulation sites where two ormore sites are being stimulated during therapy. In examples involvingmultiple stimulation sites, the stimulation pattern may be designed suchthat stimulating frequencies are not the same in all sites at whichstimulation is being delivered.

In some embodiments involving electrical stimulation utilizing eitherpercutaneous or transcutaneous (i.e., non-penetrating) electrodes, thestimulation frequencies vary within a set of ranges. For example, thestimulation frequencies applied in a stimulation pattern may include afirst or low frequency within a range of about 1 to 30 Hz, a second ormid-range frequency within a range of about 30 to 70 Hz, a third or highfrequency within a range of about 70 to 150 Hz; and/or a fourth or veryhigh frequency within a range of about 150 to 300 Hz.

TABLE 2 Electrical therapy: Frequency Table Electrical therapy:Frequency Table Frequency designation Range in Hz Low frequency  1-30Mid-range frequency 31-70 High frequency  71-150 Very high frequency151-300

In one embodiment, a stimulation frequency is varied between 2 Hz and100 Hz, in yet another embodiment, the pulse width can be adjusted frombetween 20 and 1000 microseconds to further allow therapy customization.Stimulation frequency is an important differentiator between neuralnetworks; for example, using a high frequency has been shown to bebeneficial in activating the desired trigeminal system features; incontrast, a low frequency is preferred in activating the desired vagalfeatures. Thus, in a preferred embodiment, a combination of lowfrequency and high frequency is applied respectively to activate vagaland trigeminal branches in accordance with various embodiments describedherein. In yet another embodiment, a variable frequency (e.g.,stimulating at a non-constant frequency) can be used at one or more ofthe electrodes. The variable frequency can be a sweep, and/or arandom/pseudo-random frequency variability around a central frequency(e.g., 5 Hz+/−1.5 Hz, or 100 Hz+/−10 Hz). Varying the stimulationfrequency in a random or pseudo-random way can help to prevent neuralaccommodation.

When using electrical stimulation, different combinations of pulsewidths can be used at each electrode. Pulse widths, in some examples,may range from one or more of the following: first or short pulse widthswithin a range of about 10 to 50 microseconds, or more particularlybetween 10 to 20 microseconds, 20 to 30 microseconds, 30 to 40microseconds, to 50 microseconds; second or low mid-range pulse widthswithin a range of about 50 to 250 microseconds, or more particularlybetween 50 to 70 microseconds, 70 to 90 microseconds, 90 to 110microseconds, 110 to 130 microseconds, 130 to 150 microseconds, 150 to170 microseconds, 170 to 190 microseconds, 190 to 210 microseconds, 210to 230 microseconds, or 230 to 250 microseconds; third or high mid-rangepulse widths within a range of about 250 to 550 microseconds, or moreparticularly between 250 to 270 microseconds, 270 to 290 microseconds,290 to 310 microseconds, 310 to 330 microseconds, 330 to 350microseconds, 350 to 370 microseconds, 370 to 390 microseconds, 390 to410 microseconds, 410 to 430 microseconds, 430 to 450 microseconds, 450to 470 microseconds, 470 to 490 microseconds, 490 to 510 microseconds,510 to 530 microseconds, or 530 to 550 microseconds; fourth or longpulse widths within a range of about 550 to 1000 microseconds, or moreparticularly between 550 to 600 microseconds, 600 to 650 microseconds,650 to 700 microseconds, 700 to 750 microseconds, 750 to 800microseconds, 800 to 850 microseconds, 850 to 900 microseconds, 900 to950 microseconds, or 950 to 1000 microseconds; and/or a fifth or verylong pulse widths within a range of about 1000 to 4000 microseconds ormore particularly between 1000 to 1250 microseconds, 1250 to 1500microseconds, 1500 to 1750 microseconds, 1750 to 2000 microseconds, 2000to 2250 microseconds, 2250 to 2500 microseconds, 2500 to 2750microseconds, 2750 to 3000 microseconds, 3000 to 3250 microseconds, 3250to 3500 microseconds, 3500 to 3750 microseconds, 3750 to 4000microseconds. Different embodiments can use different ranges of pulsewidths at one or more of the electrodes. The selection of thestimulation pulse width depends on the desired target fiber as well asthe output intensity. For example, given a similar intensity, activationof C type fibers generally requires a longer pulse width than activationof a myelinated Aβ fiber. In a preferred embodiment, the use of a lowmid-range pulse is used to in order to preferably activate myelinatedfibers.

TABLE 3 Electrical therapy: Pulse Width Table Electrical therapy: PulseWidth Table Range in Pulse width designation microseconds Very shortpulse 10-50 Short pulse  50-150 Low mid-range pulse 151-350 Highmid-range pulse 351-550 Long pulse  551-1000 Very long pulse 1001-4000

To stimulate the various neural structures discussed above, in someimplementations, treatment devices may be designed for positioningagainst various surfaces on or surrounding a patient's ear. Turning toFIG. 8A and FIG. 8B, an example treatment device 800 is shown includingan auricular component 802 configured to contact skin behind and arounda patient's ear. The auricular component 802, for example, may wraparound a back of an ear and include electrodes 804 for contacting skinsurfaces in front of and behind the ear. The auricular component 802 isconnected to an inner ear component 806 by a connector 808.

The connector 808, in some embodiments, is releasably connected betweenthe auricular component 802 and the inner ear component 806. Forexample, at least one of a proximal (auricular component 802 side) endor at distal (inner ear component 806) end of the connector 808 may bedesigned for releasable connection. In other embodiments, the connector808 is integrated with the auricular component 802 and inner earcomponent 806, behaving as a conduit for bridging an electricalconnection between the auricular component 802 and the inner earcomponent 806.

In some implementations, the auricular component 802 includes a numberof electrodes 804 that are configured to be in contact with the dermison and around the outer ear. The auricular component 802, in someexamples, may include an electrode positioned for proximity tovagal-related neural structures, an electrode positioned for proximityto a neural structure related to the auriculotemporal nerve, anelectrode positioned for proximity to neural structures related to thegreat auricular nerve or its branches, and/or an electrode positionedfor proximity to the lesser occipital nerve or its branches.

Additionally, the treatment device 800 includes a pulse generator orcontroller (not illustrated) for delivering a series of therapeuticelectrodes to the treatment device 800. The pulse generator may includemanagement software for controlling therapy delivery. The managementsoftware, in some examples, may include adjustment functionality forcustomizing the therapeutic output, input/output (I/O) functionality(e.g., for confirmation of therapeutic delivery), and/or metricscollection functionality for generating and retaining data such asstimulation logs, diagnostic data, and/or event data.

In some embodiments, the controller records overall therapeutic deliveryso the caregiver/clinician can measure compliance. In one example, themanagement software may notify the wearer, caregiver, clinician if thedevice has stopped delivering therapy. In a further example, the devicemay provide an indication of health status, such as reporting on thecondition of the electrodes, the conductive surface (e.g., hydrogel),and/or the analgesic. In another example, the management software mayreport data related to use, events, logs, errors, and device healthstatus. The controller, for example, may collect information forpresentation in usage reports (e.g., generated by a separate portabledevice app or computer program). In some implementations, the treatmentdevice 800 includes a unique identifier that can be used in identifyingusers and reported data so that multiple devices can be monitored usinga single software application (e.g., patients at a certain facilityand/or under supervision of a certain doctor).

In some embodiments, a pulse generator is connected to the auricularcomponent 802 by a second connector. The second connector may bereleasably connected between the auricular component 802 and the pulsegenerator. For example, at least one of a proximal (auricular component802) end or a distal (pulse generator) end of the second connector maybe designed for releasable connection. In other embodiments, the secondconnector is integrated with the auricular component 802 and the pulsegenerator, behaving as a conduit for bridging an electrical connectionbetween the auricular component 802 and the pulse generator. In furtherembodiments, a pulse generator is built into the auricular component802.

The first connector 808 and/or the second connector, in someembodiments, includes a keyed releasable connection with a correspondingport of the treatment device 800 for snug (e.g., non-spinning)connection or for assuring electrical alignment. In some embodiments,the first connector 808 and/or the second connector is designed forlocking connection with the treatment device 800. The lockingconnection, for example, may be a water-resistant locking connection toprotect against shorting due to moisture from sweat, rain, etc.

In some embodiments, the auricular component 802 and/or the inner earcomponent 806 are designed from inexpensive materials, allowing theapparatus to be disposable, thereby lowering the cost per treatment andeliminating the need for maintenance. Disposable apparatus also providesfor greater hygienics.

In an illustrative example, a treatment device such as the device 800 ofFIGS. 8A and 8B may be donned as follows. In implementations havingprotective liners on the skin adhesive and/or electrodes, remove theprotective liners before use. Apply the auricular component 802 aroundthe auricle of the patient and press against the patient's skin suchthat exposed skin adhesives and adhesives/hydrogels (or other conductiveadhesive) adhere to the skin. Next, place the inner ear component 806 inthe ear such that a first portion 806 b of the inner ear component 806is positioned outside the external ear canal in the cavum. Finally, flexor compress a second or distal portion 806 a of the inner ear component806 supporting a cymba electrode 810 until it engages with the cymba ofthe ear.

Electrodes can be made larger or combined such that, for example,multiple electrodes are combined into one large contact, such as thecontact pads 804 a, 804 b, and 804 c. A treatment device, in someembodiments, includes a set of electrodes configured to be virtuallygrouped together to form one or more effective electrodes. For example,a first grouping of electrodes can be equivalent to electrode 804 a, asecond grouping of electrodes can be equivalent to electrode 804 b, anda third grouping of electrodes can be equivalent to electrode 804 c.Grouping smaller electrodes provides the ability to have multipleelectrodes each with its own independently controlled current source,allowing for current steering, thereby providing better spatialresolution and targeting capabilities. Electrodes may be virtuallygrouped by processing circuitry.

In some implementations, a treatment device includes one or more hapticfeedback actuators between electrode pairs. The haptic feedbackactuator(s), for example, may move from a first position to a secondposition in repetitive patterns to mask sensations felt by stimulationof the electrodes. The haptic feedback actuator(s) may be configured toisolate or electrically separate conductive shunting pathways betweenelectrodes, for example between portions of conductive gel.

Turning to FIG. 9A through FIG. 9C, in some implementations, an earpieceassembly 900 includes a printed circuit board (PCB) layer havingelectrodes. A flexible PCB can include electronic components to suppresselectrical spikes as well as a component to identify and/or uniquelyidentify the PCB. Exposed conductive surfaces on the PCB can serve ascontact point to connect hydrogels or other conductive adhesivematerials to the PCB. The PCB extends forming a cable-like structure(connector) 904 to integrate an inner ear component 906 and an auricularcomponent 902 without the need for soldering and/or connecting duringassembly. The earpiece assembly 900, in some embodiments, is extremelyflexible, allowing it to easily conform to different shapes presented bythe anatomic variability of users. In some embodiments, the earpieceassembly 900 is at least partially custom printed to provide a fittedshape for the user.

In some implementations, the flexible PCB is encapsulated in aprotective covering. The protective covering can be made from a flexiblematerial such as silicone. The protective covering may be applied invarying thickness and/or densities, for example to improve comfortduring wear, to increase retention strength of the device during wear,and to protect the circuitry from damage. The encapsulation is done withat least one material. In some embodiments, the encapsulation is done atleast in using one mold and at least one molding step. The flexible PCB,for example, may be at least partially covered with a closed cell foam.

Turning to FIG. 9B, in some implementations, the auricular component 902includes a set of electrode contacts 908 a, 908 b, and 908 c. More orfewer electrode contacts may be included, and each electrode contact maybe in electrical contact with one or more electrodes of the PCB layer.The protective covering, in some implementations, includes openings toexpose contacts to electrodes. For example, electrode contact pads 908a-c may be added to exposed regions. In other implementations, theentire earpiece assembly 900 is printed, including the protective layerand the contact pads 908 a-c.

In some embodiments, the skin-contacting electrodes of the earpieceassembly 900 are formed in layers. For example, a first layer mayinclude a medical-grade double-sided conducting adhesive tape, thesecond layer may include a conductive flexible metallic and/or fabricmesh for mechanical robustness and homogenic electrical fielddistribution, and a third layer may include a self-adhesive hydrogel, orother skin-contacting conductive adhesive. In other embodiments, atwo-layer version may be provided having a first layer configured formechanical robustness and homogenic electrical field distribution and asecond layer including a self-adhesive hydrogel, or otherskin-contacting conductive adhesive. The PCB electrodes may be formedsuch that they cover a similar surface area as the skin-contactinghydrogel electrodes. In this manner, homogenic electrical fielddistribution may be achieved at the hydrogels without the need of anyadditional conductive layer.

In some implementations, a first portion 906 a of the inner earcomponent 906 and/or a second portion 906 b of the inner ear component906 includes one or more stimulation electrodes. The electrodes may beexposed (e.g., no protective layer covering) and/or one or more contactpads may be applied to the first portion 906 a and/or the second portion906 b.

The connector 904, in some implementations, is designed to curve up toallow for insertion of the inner ear component 906, as illustrated inFIG. 9C. In other implementations, the connector 904 is printed as aspring (e.g., telephone cord) to provide mobility of the inner earcomponent 906.

In some implementations, the earpiece assembly 900 connects to a pulsegenerator via a slim keyed connector. In other implementations, the PCBlayer includes controller circuitry for generating pulses.

In some implementations, a pulse generator for use with an earpiecedevice includes a battery and circuitry configured to produce therapystimulation in communication with the electrodes of the earpiece device.In some embodiments, the pulse generator includes at least one antennaconfigured to receive programming instructions encoding stimulationparameters. The system may be rechargeable to allow for long-term use.

In some embodiments, the auricular component of the earpiece device isconnected to an electrical pulse generator which produces the therapystimulation going to the electrodes on the auricular component and theinner ear component. In some implementations, the pulse generator islocated in close proximity with the auricle of the patient. For example,the pulse generator may be designed into or releasably connected to ahead apparatus similar to an over the head or back of the headheadphones band or earmuffs band. In another example, the pulsegenerator may be releasably retained in a pocket of a cap or head wrapworn by a patient. In other embodiments, the pulse generator is placedon the body of the user, for example on the pectoral region just belowthe clavicle. In another embodiment, the pulse generator can be clippedto the user's clothing or carried in the user's trousers pocket or in aspecially designed pouch. In further embodiments, the pulse generator isbuilt into the auricular component of the earpiece device.

In some embodiments, the pulse generator includes an input/output (I/O)interface for user control of the therapy. The I/O interface, forexample, may include a number of controls, such as buttons, dials, or atouch pad, for adjusting therapy. In some examples, the I/O interfacemay include one or more of a mode selection, a length of time selection,or a stimulation strength control. Separate controls, in a furtherexample, may be provided for the adjustment of the electrodes of theconcha apparatus and for the electrodes of the earpiece.

In some embodiments, the pulse generator is remotely configurable viawireless communication. In some embodiments, the wireless remote devicemay periodically request therapy status and in some embodiments thestatus, including any changes, may be communicated to a 3rd party suchas a healthcare provider who is monitoring the therapy being applied tothe user. For example, therapy provided via the pulse generator may becontrolled or adjusted at least in part using a peripheral device suchas a mobile device, a tablet, or a personal computer. For example, amode and/or stimulation strength may be adjusted by a clinical user(e.g., doctor, nurse, occupational therapist, etc.), while the timing(e.g., powering on and off and/or length of time setting) of thestimulation may be user-controlled via the I/O interface of the pulsegenerator. In another example, a software update to the pulse generatormay be delivered via wireless communication. The wireless communication,in some examples, can include radio frequency (RF) communication (e.g.,Bluetooth) or near-field communication (NFC). The wireless communicationmay be enabled via an application installed on the peripheral device.

In some embodiments, other components of the treatment device areconfigurable by or capable of communication with a peripheral device.For example, data collected by the treatment device may be transferredto the peripheral device and thereby exchanged via a computing cloudwith third parties such as healthcare professionals and/or healthcareproviders.

In some implementations, a therapeutic auricular device is designed forcontinuous use for, in some examples, at least thirty minutes, between ahalf hour and an hour, between one hour and five hours, or for acomplete workday (e.g., approximately 8 to 10 hours). However, a devicedesigned for continuous use can be utilized intermittently for shorttime intervals, or specific duty cycles. For example, a device could beactive for one 5-to-10 minute period or for several of such periods withan off time between the active periods. For example, for militarytraining and/or operations, soldiers may be provided with continuous orintermittent therapy for a number of hours. A power pack, for example,may be tethered to the therapeutic auricular device and attachedto/integrated into a variety of standard equipment, such as a militaryhelmet or air traffic controller headset, to provide adequate power forlonger term use. The power pack may include additional circuitry, suchas controller circuitry for delivering stimulations.

In some implementations, control circuitry and/or a power unit may bereleasably attachable to a therapeutic auricular device. For example, acontroller component may snap onto or otherwise engage with theauricular component of a therapeutic auricular device to providestimulation therapy. The therapeutic auricular device may be disposable,and the releasable control circuitry and/or power unit may be re-usable.

A therapeutic auricular device, in some implementations, is designed fordurability and retention throughout strenuous activities such as, insome examples, military training and/or military operations, policeoperations, and/or sports competitions (including e-sports). Thetherapeutic auricular device, for example, may include water resistancefeatures, impact resistance features, adhesive features and/oranti-slippage features.

In some embodiments, a therapeutic auricular device includes few or noinputs accessible to the wearer. For example, the therapeutic auriculardevice may include a power control button or switch. A disposabletherapeutic auricular device may include a removable battery tab that,when removed, engages power to the device and initiates therapeuticdelivery.

In some embodiments, a therapeutic auricular device includes circuitryand/or other components to integrate the therapeutic auricular devicewith other devices, such as communications devices. For example, thetherapeutic auricular device may include a wireless speaker component,wireless signal reception, and/or wireless signal transmission. Atherapeutic auricular device may include a Bluetooth or other limitedrange wireless communication module for remote therapy initiation. In anillustrative example, upon the beginning of a mission or militaryoperation, the therapeutic auricular devices of a group of individuals(e.g., military battalion, special weapons and tactics (SWAT) team,etc.) may be triggered to initiate therapy via a wireless command orsignal issued by a single master controller. The signal may be a radiofrequency (RF) signal issued to a passive or active RF component of thetherapeutic auricular device.

Turning to FIG. 10A through FIG. 10C, in some implementations, atreatment system can include a treatment device 1000 in communicationwith a network 1020 and/or one or more peripheral devices 1010. Certainperipheral devices 1010, further, may enable communication between thetreatment device 1000 and one or more third parties. Examples ofperipheral devices 1010 include a personal computer, a tablet, or phone.In some embodiments, the peripheral device(s) 1010 include afitness-monitoring device, such as a Fitbit, Apple Watch, or GarminSmartwatch. In some embodiments, the peripheral device (s) 1010 includea health-monitoring device, such as a glucose meter, a holter monitor, amotion detector, an accelerometer, an electrocardiogram (EKG) monitor,an electromyography (EMG) monitor, or an electroencephalogram (EEG)monitor. Further, the peripheral devices 1010, in some embodiments,include a remote server, server farm, or cloud service accessible viathe network 1020. Certain peripheral device(s) 1010 may communicatedirectly with the treatment device 1000 using short-range wirelesscommunications, such as a radio frequency (RF) (e.g., Bluetooth, Wi-Fi,Zigbee, etc.) or near-field communication (NFC). Certain peripheraldevice(s) 1010 may communicate with the treatment device 1000 throughanother peripheral device 1010. For example, using Bluetoothcommunications, information from the treatment device 1000 may beforwarded to a cloud service via the network 1020 (e.g., using a Wi-Fi,Ethernet, or cellular connection). The network 1020, in some examples,can include a local area network (LAN), wide area network (WAN), metroarea network (MAN) or the Internet. In some embodiments, the network isa clinical LAN used for communicating information in a medicalenvironment, such as a hospital, in a secure (e.g., HIPAA-compliant)manner.

In an example illustrated in FIG. 10A, the treatment device 1000 isshown including an auricular component 1002 connected via a connector toa pulse generator 1004, and the pulse generator 1004 is wirelesslyconnected to the peripheral device(s) 1010 and/or the network 1020. Thisconfiguration, for example, may enable a patient, caregiver, or clinicaluser to adjust settings and/or monitor treatment controlled by the pulsegenerator 1004. For example, an application running on a peripheraldevice 1010 may provide one or more adjustable controls to the user foradjusting the delivery of therapy by the pulse generator 1004 to thepatient via the auricular component 1002. Further, feedback datagathered by the auricular component 1002 and/or the pulse generator1004, such as sensor feedback, may be supplied by the pulse generator1004 to one or more of the peripheral devices 1010. The feedback, forexample, may include sensor signals related to symptoms of the patientbeing treated by the treatment device 1000. A clinical user monitoringsensor metrics related to these signals may manually adjust the deliveryof therapy accordingly using the one or more adjustable controlsprovided by the application. Further, in some implementations, thefeedback may be used by one of the peripheral devices 1010 to generate anotification for review by the patient, a caregiver, or a clinician. Thenotification, for example, may include a low power notification, adevice removed notification, or a malfunction notification. In anillustrative example, the treatment device 1000 may monitor impedancemeasurements allowing closed-loop neurostimulation. The notificationsregarding removal or malfunction, for example, may be issued upondetermining that the impedance measurements are indicative of lack of aproper contact between one or more electrodes of the treatment device1000 and tissue on or surrounding the patient's ear. The notifications,for example, may be delivered to the patient and/or one or more thirdparties via an application executing on one of the peripheral devices1010. For example, the application may issue an audible alarm, present avisual notification, or generate a haptic output on the peripheraldevice 1010. Further, in some embodiments, the application may issue anotification via a communication means, such as sending an email, textmessage, or other electronic message to one or more authorized users,such as a patient, caregiver, and/or clinician.

Conversely, in some implementations, the configuration illustrated inFIG. 10A enables automatic adjustment of therapy delivery by reviewingfeedback provided by the treatment device and/or one or more peripheraldevices 1010 (e.g., fitness monitors and/or health monitors used by thepatient). In one example, a cloud platform accessible via the network1020 may receive the feedback, review present metrics, and relayinstructions to the pulse generator 1004 (e.g., via a Wi-Fi network orindirectly via a local portable device belonging to the patient such asa smart phone app in communication with the treatment device 1000). Thepulse generator 1004, in a further example, may gather feedback from theone or more fitness monitor and/or health monitor devices 1010, analyzethe feedback, and determine whether to adjust treatment accordingly.

Turning to FIG. 10B, in some implementations, the auricular component1002 of the treatment device 1000 may further be enabled for wirelesstransmission of information with one or more peripheral devices 1010.For example, the auricular component 1002 may include a short-rangeradio frequency transmitter for sharing sensor data, alerts, errorconditions, or other information with one or more peripheral devices1010. The data, for example, may be collected in a small non-transitory(e.g., non-volatile) memory region built into the auricular component1002.

In other implementations, the pulse generator 1004 is included in theauricular component 1002 that is, they are co-located thus the need foran extension cable to connect them is not necessary. The auricularcomponent 1002 and pulse generator 1004 may be wirelessly connected toan electronic device (for example a personal computer, a tablet or aphone) 1010 and/or to a remote server 1010 via the network 1020. Inturn, in some embodiments, the electronic device 1010 is also wirelesslyconnected to a remote server via the network 1020.

As shown in FIG. 10C, different communication components of thetreatment device 1000 can be in communication with the peripheraldevice(s) 1010 or network 1020. In some implementations, the treatmentdevice 1000 includes at least one isolated port 1032 for wiredcommunication with the peripheral device 1010. The isolated port 1032,in some examples, may be a universal serial bus (USB) connection (e.g.,a mini-USB connection, a micro-USB connection, a USB-C port, etc.), anEthernet port, or a Serial ATA (SATA) connector. The isolated port 1032,for example, may be included in the pulse generator 1004 for updating asoftware version running on the pulse generator 1004 or forreprogramming treatment settings of the pulse generator 1004. Theisolated port(s) 1032 may be connected to a communications port engine1034 for enabling communications between a peripheral device 1010 andthe treatment device 1000 via the isolated port 1032. The communicationsport engine 1034 may couple the isolated port 1032 to one or moremicroprocessors 1036. For example, the communications port engine 1034may establish a direct (e.g., wired) communication link with one of theperipheral devices 1010 to transfer data 1020 from a memory 1038 to theperipheral device 1010.

Further, a wireless radio frequency (RF) antenna (e.g., transmitter ortransmitter/receiver) 1040, in some implementations, is included in thetreatment device 1000. The RF antenna 1040 can be in wirelesscommunication with the peripheral device(s) 1010 directly or via thenetwork 1020. The RF antenna 1040, in combination with processingcircuitry for generating wireless communications (e.g., anothercommunication port engine 1034 or a portion of the microprocessor(s)1036) may function as a broadcast antenna, providing information to anyRF receiver in a receiving region of the treatment device 1000. Forexample, the RF antenna 1040 may broadcast sensor data, sensor metrics,alerts, alarms, or other operating information for receipt by one ormore peripheral devices 1010. In other implementations, the RF antenna1040, in combination with additional processing circuitry, may establisha wireless communication link with a particular peripheral device 1010.The wireless communication link, in some embodiments, is a securewireless communication link (e.g., HIPAA-compliant) for sharing patientdata with the peripheral device(s) 1010. The wireless communication linkmay be used to receive control settings from a peripheral device 1010for controlling the functionality of the pulse generator 1004, forexample.

Turning to FIG. 11 , a block diagram 1100 of example components of apulse generator 1150 in communication with example components of anauricular component 1160 is shown. The multichannel pulse generatorcircuit 1150, in some embodiments, has at least one microcontroller or amicroprocessor 1110 with at least one core. When multiplemicrocontrollers or multiple cores are present, for example, one maycontrol the wireless communication 1120 and other core(s) may bededicated to control the therapy. In some implementations, a low powerprogrammable logic circuitry (e.g., field programmable gate array (FPGA)or programmable logic device (PLD)) 1112 is also provided. For example,the microcontroller 1110 may be configured to switch into a low powermode as frequently as possible while the programmable logic circuitry1112 controls therapy delivery.

In some embodiments, an inverter circuit 1145 a-n is used to generatebiphasic/bipolar pulses. In some embodiments, one inverter circuit 1145a-n is used per channel 1170 a-n, while in other embodiments, a singleinverter circuit 1145 is used for multiple channels 1170 a-n. Eachchannel 1145 a-n, for example, may target a different anatomical area(e.g., tissue region) 1148 a-n. A high voltage compliance (e.g., >50V,in other embodiments >70V, and yet in others >90V) may be used to ensurethere is enough margin on the electrical potential to generate currentdemanded by the intensity control 1142 a-n of each inverter circuit 1145a-n by providing one or more high voltage inverters 1140 a-n perinverter circuit 1145 a-n. In order to enhance safety, in someembodiments, an over current detection circuit 1144 a-n is provided ineach inverter circuit 1145 a-n. In some embodiments, an impedancemeasuring circuit 1146 a-n is provided in each inverter circuit 114 a-n.The impedance measuring circuit 1146 a-n, for example, may supporttracking impedance over time to identify failure of sufficient therapydelivery. In some examples, therapy delivery may be compromised when theelectrodes are not in contact or in good contact with the target tissue1148 a-n, when a cable or connector between the multichannel pulsegenerator 1150 is disconnected from one of the auricular component(s)1160, or where the electrodes have deteriorated or are defective.Monitoring impedance over time provides the added advantage that thecondition of the contact electrode can be followed; thus allowing thecontroller to alert the user when the contact electrodes are close totheir end of life or no longer viable.

In some embodiments, an isolated port 1118, such as a universal serialbus (USB) is used to charge the battery, and to communicate with themicrocontroller(s) 1110. The communication can be both ways, such thatinstructions or entire new code can be uploaded to themicrocontroller(s) 1110 and information stored in a memory 1122 may bedownloaded. In some embodiments, the memory 1122 or additional memorycan be added to the circuitry as an external component (e.g., inwireless or wired communication with the pulse generator 1150). Forexample, the isolated port 1118 (e.g., USB) may be used to connectmemory to the pulse generator 1150. In other embodiments, at leastportions of the memory 1122 may be internal to the microcontroller(s)1110. In some embodiments, the FPGA 1112 may also have internal memory.

In some embodiments, an external trigger circuit 1124 is included, suchthat the stimulation can be started and/or stopped via an externalsignal. In some embodiments, the external trigger signal can be passedthrough the isolated port 1118; in yet other embodiments a modified USBconfiguration (i.e., not using the standard USB pin configuration) canbe used to pass the trigger signal. Using a modified USB configurationwill force a custom USB cable to be used, thus ensuring that an externaltrigger cannot be provided by mistake using an off-the-shelf USB cable.

In some embodiments, a hardware user interface is provided forinteracting with the multichannel pulse generator 1150 via userinterface circuitry 1126. In an example, the user interface circuitry1126 can include of buttons, LEDs, haptic (e.g., piezoelectric) devicessuch as buzzers, and/or a display, or a combination of any of them. Insome embodiments, the user interface circuitry 1126 includes signalprocessing components for interpreting user interface commands deliveredvia an external device (e.g., through the wireless communications 1120).The external device, in some examples, may be a smart phone app, atablet computer, or a medical monitoring device (e.g., in a hospitalsetting).

In some embodiments, an external master clock 1128 is used to drive themicrocontroller(s) 1110 and/or the FPGA 1112. In other embodiments theclock(s) of the components can be internal or integrated or co-packagedwith the microcontroller(s) 1110 and/or the FPGA 1112. In someembodiments, one or more oscillators, including in some cases adjustableoscillators 1114 are used to set pulse parameters such as, for example,frequency and/or pulse width.

In some embodiments, the auricular component 1160 is made from a thinflex PCB or printed electronics, such that it is light weight and can beeasily bent to accommodate different anatomies. In some embodiments, theauricular component 1160 has more than one channel. The auricularcomponent 1160, or each channel thereof, may include a peak suppressingcircuit 1147 a-n and electrodes 1165 a-n to contact the skin at thelocation of the target tissue 1148 a-n. In some embodiments, theauricular component(s) 1160 includes a unique chip identifier or uniqueID chip 1149. The unique ID chip can be used to track usage as well asto prevent other non-authorized circuits from connecting to themultichannel pulse generator 1150. At least one auricular component(s)1160 is connected to the multichannel pulse generator 1150.

In an exemplary embodiment, the system utilizes feedback to monitorand/or modify the therapy. The feedback may be obtained from one or moresensors capable of monitoring one or more symptoms being treated by thetherapy. For example, upon reduction or removal of one or more symptoms,a therapeutic output may be similarly reduced or ceased. Conversely,upon increase or addition of one or more symptoms, the therapeuticoutput may be similarly activated or adjusted (increased, expanded upon,etc.). In some examples, the sensors may monitor one or more ofelectrodermal activity (e.g., sweating), movement activity (e.g.,tremors, physiologic movement), glucose level, neurological activity(e.g., via EEG), muscle activity (e.g., via EMG) and/or cardio-pulmonaryactivity (e.g., EKG, heart rate, blood pressure (systolic, diastolic,and/or mean)). Imaging techniques such as MRI and fMRI could be used toadjust the therapy in a clinical setting for a given user. In otherembodiments, imaging of pupillary changes (e.g., pupillary dilation)using, for example a common cellular phone and/or smart-glass glassescould be used to provide feedback to make therapy adjustments. In someimplementations, one or more sensors are integrated into the earpieceand/or concha apparatus. One or more sensors, in some implementations,are integrated into the pulse generator. For example, periodicmonitoring may be achieved through prompting the wearer to touch one ormore electrodes on the system (e.g., electrodes built into a surface ofthe pulse generator) or otherwise interact with the pulse generator(e.g., hold the pulse generator extended away from the body to monitortremors using a motion detector in the pulse generator). In furtherimplementations, one or more sensor outputs may be obtained fromexternal devices, such as a fitness computer, smart watch, or wearablehealth monitor.

The monitoring used may be based, in part, on a treatment setting. Forexample, EEG monitoring is easier in a hospital setting, while heartrate monitoring may be achieved by a sensor such as a pulsometer builtinto the earpiece or another sensor built into a low budget healthmonitoring device such as a fitness monitoring device or smart watch.

In an illustrative example, feedback related to electrodermal activitycould be used to monitor and detect a speed or timing of a symptomand/or therapeutic outcome. In an example, the electrodermal activitycould be sensed by electrodes on the therapeutic earpiece device. Inanother example, the electrodermal activity could be detected byelectrodes on another portion of the body and communicated to thesystem. In some embodiments the electrodermal electrode can be such thatit detects specific substances in the skin (e.g., cortisol, NOx, etc.)via electrochemical means. Elevated cortisol levels, for example, havebeen associated with predisposition to motion sickness, while increasednitric oxide metabolites (NOx) may be associated with onset of motionsickness.

In some implementations, the system can further include one or moremotion detectors, such as accelerometers or gyroscopes, that can be usedgather information to modulate the therapy. In an example, the one ormore motion detectors are configured to detect a tremor and/orphysiologic movement. In an aspect, the tremor and/or the physiologicmovement can be indicative of the underlying condition and/or thetreatment to the underlying condition. In an example, the tremor and/orphysiologic movement can be indicative of symptoms associated withsubstance withdrawal. In an aspect, feedback from glucose monitoring canbe used to modulate the therapy. In another example, motion datacollected by the one or more motion detectors may be analyzed toidentify movements of a subject likely to trigger motion sickness. Inillustration, a gyroscope may be used to determine when a wearer is notin a generally vertical orientation, such as a disoriented pilot who maynot be aiming along the horizon, to apply stimulations for treatingmotion sickness. Similarly, an accelerometer may be used to determinewhen a pilot's body is being exposed to G-forces that could lead tomotion sickness. Various motion detectors may further collect signalsindicative of air turbulence while flying and/or choppiness/swells in abody of water while on a watercraft, diving, or in a submersible vessel.

In yet other implementations, EKG can be used to assess heart rate andheart rate variability, to determine the activity of the autonomicnervous system in general and/or the relative activity of thesympathetic and parasympathetic branches of the autonomic nervoussystem, and to modulate the therapy. Autonomic nervous activity can beindicative of symptoms associated with substance withdrawal. In anaspect, the treatment device can be used to provide therapy for treatingcardiac conditions such as atrial fibrillation and heart failure. In anexample, therapy can be provided for modulation of the autonomic nervoussystem. In some implementations, the treatment device can be used toprovide therapy to balance a ratio between any combinations of theautonomic nervous system, the parasympathetic nervous system, and thesympathetic nervous system.

In an aspect, the system can monitor impedance measurements allowingclosed-loop neurostimulation. In an example, monitoring feedback can beused to alert patient/caregiver if therapy is not being adequatelydelivered and if the treatment device is removed.

Turning to FIG. 12 , a motion sickness response sensory input signal(s)is carried out via a Motion Sickness Triggering Pathway 1200. Althoughmany brain regions or nuclei are involved in the response, the NucleusTractus Solitarius (NTS) 104 along with the Raphe Nucleus (RN) 16, LocusCoeruleus (LC) 108, Parabrachial Nucleus (PbN) 114 and theParaventricular Nucleus PVN 206 (of FIGS. 2B and 13 ) are the maindrivers of these pathways. The autonomic response triggering motionsickness starts with incoming sensory inputs 1212, which are integratedin the Nucleus Tractus Solitarius (NTS) 104. Sensory input signalsproduced from the Visual Cortex 1206 and Additional SomatosensoryAfferents 1208 are processed and integrated in the NTS 104. Integratedsignals are then compared with expected models, which may be stored inthe Hippocampus 138 and/or the vestibular cortex (e.g., vestibularnuclei 1204) as Cortical Areas Processing Vestibular Inputs 1202.

These integrated signals serve as the reference against which internalmodels are compared 1210. Data suggests that these internal models arestored in areas involved in spatial orientation as well as motionawareness such as, for example, the hippocampus 138 and the vestibularcortex 1202, which include cortical areas activated in response tovestibular sensory system stimuli, including vestibular mismatchactivity. When a mismatch occurs, e.g., between an integrated signal anda corresponding internal model, an autonomic response 1214 is elicited.This autonomic response 1214 involves brainstem areas such as, e.g., theRaphe Nuclei (RN) 106, the Locus Coeruleus (LC) 108, the PeriaqueductalGray (PAG), the Nucleus Basalis (NBM), the Nucleus Ambiguous (NA), theVentral Tegmental Area (VTA), the Parabrachial Nucleus (PbN) 114, andthe Pedunculopontine Nucleus (PPN), as well as hypothalamic areas 132such as, e.g., the Paraventricular Nucleus (PVN) and the Arcuate Nucleus(ARC).

To intervene against errant autonomic response brought about by motionsickness, turning to FIG. 13 , a motion sickness intervention pathway1300 may be activated. The LC 108 is the main producer of Norepinephrine(NE) in the Central Nervous System (CNS). By activating LC neurons, theavailability of central NE is increased. This increase in NE can be seenas producing a similar effect of that of the sympathomimeticsinterventions, thus counteracting the inhibition of LC-NE circuitsmanifested in motion sickness. Further, the vestibular nuclei (VN) 1204afferent serotonergic neurons from the RN 106 produce an inhibitoryeffect in VN activity. This decrease in VN activity decreases the VNefferent signals involved in the triggering of motion sickness symptoms.Further, by increasing pituitary 208 activity via the PVN 206, anincrease in peripheral circulating β endorphins 1302 is produced, which,for example, mimics the abovementioned pharmacological intervention withLoperamide.

Turning to FIG. 14 , a stimulation flow diagram 1400 illustratesstimulation mechanisms for mitigating (e.g., controlling and/oralleviating) motion sickness symptoms 1410 using a treatment device suchas the treatment device 800 of FIG. 8A or the treatment device 900 ofFIG. 9A. The stimulation mechanisms are produced by a first stimulation1402 a and a second stimulation 1402 b. The first and secondstimulations 1402, in some embodiments, are temporally separated (e.g.,in overlapping or non-overlapping stimulations). In some embodiments,the first and second stimulations 1402 are physically separated (e.g.,using a different electrode or set of electrodes contacting a differentlocation on the patient). The first and second stimulations 1402, forexample, may be provided via the motion sickness intervention pathways1300 discussed in relation to FIG. 13 . According to the motion sicknessintervention pathways 1300, the first stimulation 1402 a and/or thesecond stimulation 1402 b may be configured to stimulate the ABVN 118which projects to the NTS 104 and/or the ATN 130 which has a pathway tothe NTS 104 via the TCC 102.

Responsive to a first stimulation 1402 a, in some embodiments, 5-HTavailability is increased (1404). Increasing 5-HT availability 1404leads to an increase in BDNF expression. The BDNF, in turn, may functionto protect monoamine neurotransmitter neurons and assist the monoamineneurotransmitter neurons to differentiate. The 5-HT availability mayincrease, for example, as activity in the RN 106 is unregulated (seemotion sickness intervention pathways 1300 of FIG. 13 ). This increasein 5-HT is qualitatively comparable with the Rizatriptan therapymentioned above.

Further, in some implementations, the first stimulation 1402 a increasesperipheral circulating β endorphins 1408 (e.g., as described in relationto the β endorphins 1302 of FIG. 13 ). In some embodiments, the secondstimulation 1402 b also increases peripheral circulating β endorphins1408.

In all, the combined stimulation mechanisms of FIG. 14 may qualitativelymimic at least three pharmacological interventions that are known tohave a positive outcome when treating motion sickness. The mainadvantage of applying the stimulation mechanisms over these threepharmacological interventions is that it is not systemicallyadministered, it has no known side effects such as drowsiness, forexample, and it is not addictive.

In some implementations, the second stimulation 1402 b increases centralNE availability (1406). As discussed in relation to FIG. 13 , forexample, activation of the LC through stimulation of the NTS 104 resultsin greater central NE availability.

In some embodiments, providing the first stimulation 1402 a andproviding the second stimulation 1402 b involves providing a series ofsimultaneous and/or synchronized, and/or interleaved stimulation pulses.Each of the first stimulation 1402 a and the second stimulation 1402 bmay be applied using the same or different parameters. The parameters,in some examples, may include pulse frequency (e.g., low, mid-range,high or very high) and/or pulse width. Further, the parameters mayindicate electrode pairs for producing biphasic pulses. In a firstillustrative example, the first stimulation may be applied using a lowfrequency, while the second stimulation is applied using a mid-range orhigh frequency. Conversely, in a second illustrative example, the firststimulation may be applied using a mid-range frequency, while the secondstimulation is applied using a low frequency. Other combinations of low,mid-range, high, and/or very high frequency stimulations are possibledepending upon the patient and the disorder being treated. Therapy maybe optimized according to the needs of individual patients includingcustom stimulation frequency, custom pulse width, custom stimulationintensity (amplitude), and/or independently controlled stimulationchannels.

Turning to FIG. 15 , a WANS apparatus 1500 includes a forward portion1502 including a conductive adhesive region 1510 and a rear portion 1504including conductive adhesive regions 1506 and 1508. The conductiveadhesive region 1510 of the forward portion 1502, for example, maycorrespond to a first electrode. Similarly, the conductive adhesiveregion 1506 may correspond to a second electrode, and the conductiveadhesive region 1508 may correspond to a third electrode.

The conductive adhesive region 1510, in some implementations, isconfigured to contact skin of a wearer in a region of nerve structuresof the auriculotemporal nerve (ATN) and/or nerve structures connected tothe ATN, such that delivery of therapeutic stimulation via theconductive adhesive region 1510 modulates ATN activity. Turning to FIG.16A and FIG. 16B, for example, ATN 1602 is illustrated in relation to anear 1600 of a person (FIG. 16A), running generally in front of the ear1600, as well as in relation, skeletally (FIG. 16B), to an ear canal1610. In an illustrative example, an electrode in electricalcommunication with the conductive adhesive region 1506 may be positionedin proximity to the temporomandibular joint.

In some embodiments, the conductive adhesive region 1506 is configuredto contact skin of a wearer in a region of nerve structures of theauricular branch of the vagus nerve (ABVN) and/or nerve structureconnected to the ABVN such that delivery of therapeutic stimulations viathe conductive adhesive region 1506 modulates ABVN activity. As shown inFIG. 16A through FIG. 16D for example, ABVN 1604 is illustrated as itsurfaces (FIG. 16D) through the mastoid canaliculus (MsC) 1612 (e.g.,Arnold's canal) and in relation to the ear 1600 (FIG. 16A), in relationto the ear canal 1610 (FIG. 16B) and in relation to the back of the ear(FIG. 16C). Turning to FIG. 17 , posterior auricular nerve 1700 meets abranch of the ABVN, providing another target for ABVN stimulation. In anillustrative example, an electrode in electrical communication with theconductive adhesive region 1506 may be positioned in proximity to theMsC.

The conductive adhesive region 1508, in some embodiments, is configuredto contact skin of the patient as a return electrode, thereby forming anelectrical circuit across the tissue with the electrodes correspondingto each of the forward conductive adhesive region 1510 and the rearconductive adhesive region 1506. Although illustrated as a single returnelectrode (e.g., region 1508) for each positive electrode correspondingto adhesive region 1510 and adhesive region 1506, in other embodiments,separate return electrodes may be provided for each positive electrode.In further embodiments, three or more return electrode paths may beprovided for the two positive electrodes. Other combinations arepossible.

Turning to FIG. 8B, a conductive adhesive region may similarly beprovided to create an electrical communication path from an electrodepositioned on the first portion 806 b of the inner ear component 806 ofthe WANS 800 to skin of the wearer in an anterior part of the ear canal.Turning to FIG. 18 , such an electrode, for example, may be positionedto stimulate the nervus meatus acustici externi branch 1800 of the ATN1602.

As illustrated in FIG. 15 , a non-conductive adhesive may be providedgenerally in regions 1512 a (e.g., around conductive adhesive 1510) and1512 b (e.g., between conductive regions 1506 and 1508, around region1508, and at least partially around region 1506). The non-conductiveadhesive, for example, may be used to electrically isolate conductiveregions created through electrical communication between electrodes andthe conductive adhesive 1506, 1508, and 1510. In this manner, thenon-conductive adhesive may be used to avoid short-circuiting of theWANS apparatus 1500. The non-conductive adhesive, in some examples, maybe deposited (e.g., sprayed, three-dimensionally printed, etc.) on oneor more exterior surfaces of the WANS device 1500. In some embodiments,the non-conductive adhesive is a double-sided tape that is positionedmanually or robotically on the WANS apparatus 1500. Rather than using anon-conductive adhesive, in other embodiments, a gripping materialand/or pattern is molded into and/or three-dimensionally printed ontosections of the WANS apparatus 1500. For example, three-dimensionaladhesive microstructures may be provided on the surface of the WANS 1500to increase retention of the WANS apparatus 1500 about the wearer's ear.

In some implementations, one or more liners 1514 are placed over theadhesive regions to maintain stickiness and cleanliness of the adhesivematerial prior to wearing. As illustrated in FIG. 15 , for example, aforward liner 1514 a is illustrated as covering the adhesive regions1510 and 1512 a of the forward section 1502, and a rear liner 1514 b isillustrated as covering the adhesive regions 1506, 1508, and 1512 b ofthe rear section 1504. In other embodiments, a single liner may beprovided to cover all adhesive regions of the WANS 1500.

Reference has been made to illustrations representing methods andsystems according to implementations of this disclosure. Aspects thereofmay be implemented by computer program instructions. These computerprogram instructions may be provided to a processor of a general-purposecomputer, special purpose computer, or other programmable dataprocessing apparatus to produce a machine, such that the instructions,which execute via the processor of the computer or other programmabledata processing apparatus, create means for implementing thefunctions/operations specified in the illustrations.

One or more processors can be utilized to implement various functionsand/or algorithms described herein. Additionally, any functions and/oralgorithms described herein can be performed upon one or more virtualprocessors, for example on one or more physical computing systems suchas a computer farm or a cloud drive.

Aspects of the present disclosure may be implemented by hardware logic(where hardware logic naturally also includes any necessary signalwiring, memory elements and such), with such hardware logic able tooperate without active software involvement beyond initial systemconfiguration and any subsequent system reconfigurations. The hardwarelogic may be synthesized on a reprogrammable computing chip such as afield programmable gate array (FPGA), programmable logic device (PLD),or other reconfigurable logic device. In addition, the hardware logicmay be hard coded onto a custom microchip, such as anapplication-specific integrated circuit (ASIC). In other embodiments,software, stored as instructions to a non-transitory computer-readablemedium such as a memory device, on-chip integrated memory unit, or othernon-transitory computer-readable storage, may be used to perform atleast portions of the herein described functionality.

Various aspects of the embodiments disclosed herein are performed on oneor more computing devices, such as a laptop computer, tablet computer,mobile phone or other handheld computing device, or one or more servers.Such computing devices include processing circuitry embodied in one ormore processors or logic chips, such as a central processing unit (CPU),graphics processing unit (GPU), field programmable gate array (FPGA),application-specific integrated circuit (ASIC), or programmable logicdevice (PLD). Further, the processing circuitry may be implemented asmultiple processors cooperatively working in concert (e.g., in parallel)to perform the instructions of the inventive processes described above.

The process data and instructions used to perform various methods andalgorithms derived herein may be stored in non-transitory (i.e.,non-volatile) computer-readable medium or memory. The claimedadvancements are not limited by the form of the computer-readable mediaon which the instructions of the inventive processes are stored. Forexample, the instructions may be stored on CDs, DVDs, in FLASH memory,RAM, ROM, PROM, EPROM, EEPROM, hard disk or any other informationprocessing device with which the computing device communicates, such asa server or computer. The processing circuitry and stored instructionsmay enable the pulse generator 1004 of FIG. 10A through FIG. 10C or thepulse generator 1150 of FIG. 11 to perform various methods andalgorithms described above. Further, the processing circuitry and storedinstructions may enable the peripheral device(s) 1010 of FIG. 10Athrough FIG. 10C to perform various methods and algorithms describedabove.

These computer program instructions can direct a computing device orother programmable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablemedium produce an article of manufacture including instruction meanswhich implement the function/operation specified in the illustratedprocess flows.

Embodiments of the present description rely on network communications.As can be appreciated, the network can be a public network, such as theInternet, or a private network such as a local area network (LAN) orwide area network (WAN) network, or any combination thereof and can alsoinclude PSTN or ISDN sub-networks. The network can also be wired, suchas an Ethernet network, and/or can be wireless such as a cellularnetwork including EDGE, 3G, 4G, and 5G wireless cellular systems. Thewireless network can also include Wi-Fi, Bluetooth, Zigbee, or anotherwireless form of communication. The network, for example, may be thenetwork 1020 as described in relation to FIG. 10A through FIG. 10C.

The computing device, such as the peripheral device(s) 1010 of FIGS.10A-10C, in some embodiments, further includes a display controller forinterfacing with a display, such as a built-in display or LCD monitor. Ageneral purpose I/O interface of the computing device may interface witha keyboard, a hand-manipulated movement tracked I/O device (e.g., mouse,virtual reality glove, trackball, joystick, etc.), and/or touch screenpanel or touch pad on or separate from the display.

A sound controller, in some embodiments, is also provided in thecomputing device, such as the peripheral device(s) 1010 of FIG. 10Athrough FIG. 10C, to interface with speakers/microphone therebyproviding audio input and output.

Moreover, the present disclosure is not limited to the specific circuitelements described herein, nor is the present disclosure limited to thespecific sizing and classification of these elements. For example, theskilled artisan will appreciate that the circuitry described herein maybe adapted based on changes on battery sizing and chemistry or based onthe requirements of the intended back-up load to be powered.

Certain functions and features described herein may also be executed byvarious distributed components of a system. For example, one or moreprocessors may execute these system functions, where the processors aredistributed across multiple components communicating in a network suchas the network 1020 of FIG. 10A through FIG. 10C. The distributedcomponents may include one or more client and server machines, which mayshare processing, in addition to various human interface andcommunication devices (e.g., display monitors, smart phones, tablets,personal digital assistants (PDAs)). The network may be a privatenetwork, such as a LAN or WAN, or may be a public network, such as theInternet. Input to the system may be received via direct user input andreceived remotely either in real-time or as a batch process.

Although provided for context, in other implementations, methods andlogic flows described herein may be performed on modules or hardware notidentical to those described. Accordingly, other implementations arewithin the scope that may be claimed.

In some implementations, a cloud computing environment, such as GoogleCloud Platform™, may be used perform at least portions of methods oralgorithms detailed above. The processes associated with the methodsdescribed herein can be executed on a computation processor of a datacenter. The data center, for example, can also include an applicationprocessor that can be used as the interface with the systems describedherein to receive data and output corresponding information. The cloudcomputing environment may also include one or more databases or otherdata storage, such as cloud storage and a query database. In someimplementations, the cloud storage database, such as the Google CloudStorage, may store processed and unprocessed data supplied by systemsdescribed herein.

The systems described herein may communicate with the cloud computingenvironment through a secure gateway. In some implementations, thesecure gateway includes a database querying interface, such as theGoogle BigQuery platform.

While certain embodiments have been described, these embodiments havebeen presented by way of example only and are not intended to limit thescope of the present disclosures. Indeed, the novel methods, apparatusesand systems described herein can be embodied in a variety of otherforms; furthermore, various omissions, substitutions and changes in theform of the methods, apparatuses and systems described herein can bemade without departing from the spirit of the present disclosures. Theaccompanying claims and their equivalents are intended to cover suchforms or modifications as would fall within the scope and spirit of thepresent disclosures.

1. A method for inhibiting, reducing or eliminating motion sicknessusing neuromodulation, the method comprising: placing at least one firstelectrode on, over, or adjacent to one or more first neural structuresof a first set of neural structures, wherein each electrode of the atleast one first electrode is placed against or at least partially into arespective first tissue region on or substantially adjacent an ear of asubject; placing at least one second electrode on, over or adjacent toone or more second neural structures of a second set of neuralstructures, wherein each electrode of the at least one second electrodeis placed against or at least partially into a respective second tissueregion on or substantially adjacent the ear of the subject; anddelivering, by a pulse generator, therapeutic stimulation pulses fortreating motion sickness of the subject without causing sedation and/ordrowsiness, wherein delivering the therapeutic stimulation pulsescomprises delivering a first series of stimulation pulses to the atleast one first electrode, wherein the first series of stimulationpulses is configured to modulate peripheral activity via modulatingcentral neural autonomic structures, and delivering a second series ofstimulation pulses to the at least one second electrode, wherein thesecond series of stimulation pulses is configured to modulate one ormore areas in a brain stem of the subject.
 2. The method of claim 1,wherein modulating the central neural autonomic structures comprisesmodulating the paraventricular hypothalamic nucleus (PVN) to stimulateincreased activity in the pituitary.
 3. The method of claim 1, whereinmodulating the peripheral activity comprises producing an increase inperipheral circulating beta-endorphins.
 4. The method of claim 33,wherein the second series of stimulation pulses is further configured tomodulate activity in the vestibular nuclei (VN).
 5. The method of claim1, wherein at least one of the first set of neural structures or thesecond set of neural structures are in direct or indirect communicationwith an auriculotemporal nerve (ATN).
 6. The method of claim 1, whereinat least one of the first set of neural structures or the second set ofneural structures are in direct or indirect communication with anauricular branch of a vagus nerve (ABVN).
 7. The method of claim 1,wherein at least one of the first series of stimulation pulses and thesecond series of stimulation pulses is configured to increase serotonin(5-HT) availability.
 8. The method of claim 1, wherein: the first seriesof stimulation pulses are delivered at one or more low frequenciesselected from a first frequency range up to 30 Hertz; and the secondseries of stimulation pulses are delivered at i) one or more mid-rangefrequencies selected from a second frequency range from 31 Hertz to 70Hertz or ii) one or more high frequencies selected from a thirdfrequency range from 71 Hertz to 150 Hertz.
 9. The method of claim 1,further comprising: monitoring, by one or more sensors, physicalmovements of the subject or a device worn by the subject; whereindelivering the therapeutic stimulation pulses comprises initiating thetherapeutic stimulation pulses responsive to analyzing, by controlcircuitry, at least one feedback signal from the one or more sensors toidentify one or more situational triggers indicative of likelihood ofmotion sickness.
 10. The method of claim 9, wherein a device comprisingthe one or more sensors is separate from a therapeutic neuromodulationsystem comprising the pulse generator, the at least one first electrode,and the at least one second electrode.
 11. The method of claim 9,wherein the one or more sensors comprises at least one of a motiondetector, an accelerometer, or a gyroscope.
 12. The method of claim 11,wherein the one or more situational triggers comprise at least one ofexposure to G-forces, exposure to turbulence, flying in a substantiallynon-vertical orientation, or exposure to choppiness and/or swells whileon or in water.
 13. The method of claim 1, wherein: a virtual reality(VR) device comprises the at least one first electrode and the at leastone second electrode; and delivering the therapeutic stimulation pulsescomprises initiating the therapeutic stimulation pulses based onactivating a VR program.
 14. The method of claim 1, wherein treatingmotion sickness comprises treating space adaptation syndrome in amicrogravity environment. 15.-27. (canceled)
 28. The method of claim 1,wherein: a given electrode of the at least one first electrode is placedbehind the auricle; and a given neural structure of the one or morefirst neural structures corresponding to the given electrode is theauricular branch of the vagus nerve (ABVN) near a point at which theABVN surfaces through the mastoid canaliculus (MsC).
 29. The method ofclaim 1, wherein: a given electrode of the at least one second electrodeis placed forward of the auricle; and a given neural structure of theone or more second neural structures is a branch of the auriculotemporalnerve (ATN).
 30. The method of claim 29, wherein the branch of the ATNis the nervus meatus acustici externi.
 31. The method of claim 1,wherein placing the at least one first electrode and placing the atleast one second electrode comprises donning, by the subject, aprotective helmet comprising one or more of the at least one firstelectrode and one or more of the at least one second electrode.
 32. Themethod of claim 1, wherein: a head-mounted neurostimulation devicecomprises the at least one first electrode, the at least one secondelectrode, and the pulse generator; and placing the at least one firstelectrode and placing the at least one second electrode comprisesdonning, by the subject, the head-mounted neurostimulation device. 33.The method of claim 1, wherein modulating the one or more areas in thebrain stem comprises modulating the locus coeruleus (LC) to increaseavailability of central norepinephrine (NE).
 34. The method of claim 1,wherein treating motion sickness comprises treating spatialdisorientation.